Glucosylceramide synthase inhibition for the treatment of collapsing glomerulopathy and other glomerular disease

ABSTRACT

A method of treating a glomerular disease selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis and membranous nephropathy in a subject comprises administering to the subject an effective amount of a glucosylceramide synthase inhibitor.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 13/055,036, filed Mar. 17, 2011, now U.S. Pat. No. 8,389,517, issued Mar. 6, 2013, which is the U.S. National Stage of International Application No. PCT/US2009/051864, filed Jul. 27, 2009, published in English, which claims the benefit under 35 U.S.C. §119 or 365 of U.S. Provisional Application No. 61/137,214, filed Jul. 28, 2008. The entire teachings of the above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Many diseases affect kidney function by attacking the glomeruli, the tiny units within the kidney where blood is cleaned. Glomerular diseases include many conditions with a variety of genetic and environmental causes, but they fall into two major categories:

1. Glomerulonephritis describes the inflammation of the membrane tissue in the kidney that serves as a filter, separating wastes and extra fluid from the blood.

2. Glomerulosclerosis describes the scarring or hardening of the tiny blood vessels within the kidney.

Although glomerulonephritis and glomerulosclerosis have different causes, they can both lead to kidney failure.

Glomerular diseases damage the glomeruli, letting protein and sometimes red blood cells leak into the urine. Sometimes a glomerular disease also interferes with the clearance of waste products by the kidney, so they begin to build up in the blood. Furthermore, loss of blood proteins like albumin into the urine can result in a fall in their level in the bloodstream. In normal blood, albumin acts like a sponge, drawing extra fluid from the body into the bloodstream, where it remains until the kidneys remove it. But when albumin leaks into the urine, the blood loses its capacity to absorb extra fluid from the body. Fluid can accumulate outside the circulatory system in the face, hands, feet, or ankles and cause swelling. A number of different specific glomerular diseases are discussed below:

Mesangial proliferative glomerulonephritis is a kidney disorder characterized by swelling and blood in the urine (dark urine). It is caused by inflammation of an internal kidney structure (glomerulus), and specifically an increase in number of certain glomerular cells (mesangial cells), accompanied by antibody deposits in the mesangium layer of the glomerular capillary.

Mesangial proliferative glomerulonephritis is a form of glomerulonephritis (inflammation of the kidney glomeruli). The mesangial cells (part of the glomerular capillaries) increase in size and number, giving the glomeruli a lumpy appearance.

The mechanism that triggers the disorder is unknown, but it is believed to be some type of immune response, because inflammation of the glomeruli is associated with deposits of antibodies.

This is a relatively uncommon disorder. The term mesangial proliferative glomerulonephritis is actually a description of the microscopic pattern of this disease.

It may be seen more commonly in lupus patients who develop glomerulonephritis, and in patients who have IgA mediated kidney disease. It can affect both adults and children. Men may be affected slightly more often than women.

The disorder usually causes nephrotic syndrome (protein loss in the urine and swelling of the body). It may be present as acute, chronic, or rapidly progressive glomerulonephritis, and may progress to chronic kidney failure. Rapidly progressive glomerulonephritis (also known as crescentic glomerulonephritis) is a form of kidney disease that causes damage to the small structures (glomeruli) inside the kidneys that help filter waste and fluids from blood to form urine. The disease leads to a rapid loss of kidney function.

Collapsing glomerulopathy is a proliferative disease defined by segmental or global wrinkling of the glomerular basement membranes associated with podocyte proliferation. These lesions are particularly poor responders to standard therapies. First described as an idiopathic disorder or following HIV infection, it is now associated with a broad group of diseases and different pathogenetic mechanisms, which participate in podocyte injury and mitogenic stimulation. Because of this etiologic heterogeneity, there is clear need for new therapeutic approaches to target each variant of this entity.

Proliferative lupus nephritis is the name given to a kidney disease caused by systemic lupus erythematosus, and it occurs when autoantibodies form or are deposited in the glomeruli, causing inflammation. Ultimately, the inflammation may create scars that keep the kidneys from functioning properly.

Conventional treatment for lupus nephritis includes a combination of two drugs, cyclophosphamide, a cytotoxic agent that suppresses the immune system, and prednisolone, a corticosteroid used to reduce inflammation. A newer immunosuppressant, mychophenolate mofetil (MMF), has been used instead of cyclophosphamide. Preliminary studies indicate that MMF may be as effective as cyclophosphamide and has milder side effects.

Membranous nephropathy, also called membranous glomerulopathy, is the second most common cause of the nephrotic syndrome (proteinuria, edema, high cholesterol) in U.S. adults after diabetic nephropathy. Diagnosis of membranous nephropathy requires a kidney biopsy, which reveals unusual deposits of immunoglobulin G and complement C3, substances created by the body's immune system. Fully 75 percent of cases are idiopathic, which means that the cause of the disease is unknown. The remaining 25 percent of cases are the result of other diseases such as systemic lupus erythematosus, hepatitis B or C infection, or some forms of cancer. Drug therapies involving penicillamine, gold, or captopril have also been associated with membranous nephropathy. About 20 to 40 percent of patients with membranous nephropathy progress, usually over decades, to total kidney failure, but most patients experience either complete remission or continued symptoms without progressive kidney failure. Doctors disagree about how aggressively to treat this condition, since about 20 percent of patients recover without treatment. ACE inhibitors and ARBs are generally used to reduce proteinuria. Additional medication to control high blood pressure and edema is frequently required. Some patients benefit from steroids, but this treatment does not work for everyone. Additional immunosuppressive medications are helpful for some patients with progressive disease.

There is a need for agents and methods for preventing the onset of, or slowing the progression of glomerular diseases, such as the ones described above.

SUMMARY OF THE INVENTION

The present invention is directed to a method of treating a glomerular disease selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis and membranous nephropathy in a subject, comprising administering to the subject an effective amount of a glucosylceramide synthase inhibitor.

Also included in the present invention is the use of glucosylceramide synthase inhibitors disclosed herein for treating a glomerular disease selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis and membranous nephropathy in a subject.

The present invention also includes the use of glucosylceramide synthase inhibitors disclosed herein for the manufacture of a medicament for treating a subject having a glomerular disease selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis and membranous nephropathy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is micrographs showing hematoxylin and eosin stained kidney sections from early stage animals (left) or late stage animals (right). Arrow: normal glomerulus; arrowhead: injured glomerulus; *: microcyst.

FIG. 1B is bar graphs showing kidney (left) and serum (right) glucosylceramide levels of Tg26 transgenic mouse and control mouse, respectively, measured by LC/MS analysis. Kidney samples were normalized to total phosphate content. Mean values+/−SEM are shown.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a method of treating a glomerular disease selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis and membranous nephropathy that comprises administering an effective amount of a glucosylceramide synthase inhibitor to a subject.

Glucosylceramides are precursors to gangliosides, such as GM1, GM2 and GM3, which are glycosphingolipids (GSLs) comprised of ceramide and at least one acidic sugar. Glucosylceramide synthase is an enzyme in the biosynthesis of glucosylceramides. Gangliosides are generally found in the outer leaflet of the plasma membrane (Nojri et al., Proc. Natl. Acad. ScL USA 83:782 (1986)). Gangliosides are involved in cell signaling and act as modulators of receptor activity (Yamashita et al., Proc. Natl. Acad. ScL USA 100(6):3445 (2003)). A number of GSLs are derived from glucosylceramide, which is enzymatically formed from ceramide and UDP-glucose. The formation of glucosylceramide is catalyzed by glucosylceramide synthase.

As used herein, “glucosylceramide synthase inhibitors” are defined as an agent which is capable of inhibiting glucosylceramide synthesis. A number of glucosylceramide synthase inhibitors have been identified. One class of glucosylceramide synthase inhibitors includes 2-acylaminopropoanol derivatives, disclosed in International Patent Application No. PCT/US2008/006906, the entire teachings of which are incorporated herein by reference. Examples of glucosylceramide inhibitors disclosed in PCT/US2008/006906 are described below.

In one embodiment, the glucosylceramide synthase inhibitor is represented by Structural Formula (I),

or a pharmaceutically acceptable salt thereof.

A first set of values and preferred values for the variables in Structural Formula (I) is provided in the following paragraphs:

R¹ is a substituted or unsubstituted aryl group, such as a substituted or unsubstituted phenyl group. Preferably, R¹ is an aryl group optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, Ar¹, —OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰, —NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰, —NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_(o)—Ar¹, —V_(o)—OR³⁰, —V_(o)—O(haloalkyl), —V_(o)—SR³⁰, —V_(o)—NO₂, —V_(o)—CN, —V_(o)—N(R³¹)₂, —V_(o)—NR³¹C(O)R³⁰, —V_(o)—NR³¹CO₂R³², —V_(o)—N(R³¹)C(O)N(R³¹)₂, —V_(o)—C(O)R³⁰, —V_(o)—C(S)R³⁰, —V_(o)—CO₂R³⁰, —V_(o)—OC(O)R³⁰, —V_(o)—C(O)N(R³¹)₂—, —V_(o)—S(O)₂R³⁰, —V_(o)—SO₂N(R³¹)₂, —V_(o)—S(O)R³², —V_(o)—SO₃R³⁰, —V_(o)—NR³¹SO₂N(R³¹)₂, —V_(o)—NR³¹SO₂R³², —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—NR³¹)₂, —NR³¹C(O)—V_(o)—N(R³¹)₂, —NR³¹C(O)—V_(o)—Ar¹, —C(O)—V_(o)—N(R³¹)₂, —C(O)—V_(o)—Ar¹, —C(S)—V_(o)—N(R³¹)₂, —C(S)—V_(o)—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_(o)—Ar¹, —O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_(o)—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂, —C(O)N(R³¹)—V_(o)—Ar¹, —S(O)₂—V_(o)—N(R³¹)₂, —S(O)₂—V_(o)—Ar¹, —SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_(o)—Ar¹, —S(O)—V_(o)—N(R³¹)₂, —S(O)—V_(o)—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_(o)—Ar¹, —NR³¹SO₂—V_(o)—N(R³¹)₂, —NR³¹SO₂—V_(o)—Ar¹, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or [CH₂]_(q)—. More preferably, R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, and —[CH₂]_(q)—. Even more preferably, R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkoxy(C1-C6)alkoxy, C1-C6 haloalkoxy(C1-C6)alkoxy, C1-C6 hydroxyalkoxy and —O—[CH₂]_(p)—O—. Even more preferably, R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅ and —O—[CH₂]_(p)—O—.

Y is —H, a hydrolyzable group, or a substituted or unsubstituted alkyl group. Examples of hydrolyzable groups include —C(O)R, —C(O)OR, —C(O)NRR′, C(S)R, —C(S)OR, —C(O)SR or —C(S)NRR′. Preferably, Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′; more preferably, —H.

R² and R³ are each independently —H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aryl group, or R² and R³ taken together with the nitrogen atom of —N(R²R³) form a substituted or unsubstituted non-aromatic heterocyclic ring, or a substituted or unsubstituted bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms. Preferably, R² and R³ taken together with the nitrogen atom of —N(R²R³) form a 5- or 6-membered, optionally-substituted non-aromatic heterocyclic ring; or, R² and R³ taken together with the nitrogen atom of —N(R²R³) form a substituted or unsubstituted bridged heterobicyclic ring comprising 6 or 7 ring carbon atoms and 1 or 2 ring nitrogen atoms. More preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group,

Even more preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl, piperidinyl, azepinyl group,

Even more preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl group,

Suitable substituents for the aliphatic and aryl groups represented by R² and R³, and suitable substituents for the non-aromatic heterocyclic ring or the bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms represented by —N(R²R³) each independently include halogen, alkyl, haloalkyl, —OR⁴⁰, —O(haloalkyl), —SR⁴⁰, —NO₂, —CN, —N(R⁴¹)₂, —NR⁴¹C(O)R⁴⁰, —NR⁴¹C(O)OR⁴², —N(R⁴¹)C(O)N(R⁴¹)₂, —C(O)R⁴⁰, —C(S)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —C(O)N(R⁴¹)₂, —S(O)₂R⁴⁰, —SO₂N(R⁴¹)₂, —S(O)R⁴², —SO₃R⁴⁰, Ar², V₂—Ar², —V₂—OR⁴⁰, —V₂—O(haloalkyl), —V₂—SR⁴⁰, —V₂—NO₂, —V₂—CN, —V₂—NR⁴¹)₂, —V₂—NR⁴¹C(O)R⁴⁰, —V₂—NR⁴¹CO₂R⁴², —V₂—N(R⁴¹)C(O)N(R⁴¹)₂, —V₂—C(O)R⁴⁰, —V₂—C(S)R⁴⁰, —V₂—CO₂R⁴⁰, —V₂—OC(O)R⁴⁰, —V₂—C(O)N(R⁴¹)₂—, —V₂—S(O)₂R⁴⁰, —V₂—SO₂N(R⁴¹)₂, —V₂—S(O)R⁴², —V₂—SO₃R⁴⁰, —O—V₂—Ar² and —S—V₂—Ar². Preferably, suitable substituents for the non-aromatic heterocyclic ring or the bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms represented by —N(R²R³) each independently include halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. More preferably, suitable substituents for the non-aromatic heterocyclic ring or the bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms represented by —N(R²R³) each independently include halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

X is —(CR⁵R⁶)_(n)-Q-; Q is —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —C(S)S—, —C(O)NR⁷—, —NR⁷—, —NR⁷C(O)—, —NR⁷C(O)NR⁷—, —OC(O)—, —SO₃—, —SO—, —S(O)₂—, —SO₂NR⁷—, or —NR⁷SO₂—; and R⁴ is —H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aryl group. Preferably, Q is —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —C(S)S—, —C(O)NR⁷—, —NR⁷C(O)NR⁷—, —OC(O)—, —SO₃—, —SO—, —S(O)₂—, —SO₂NR⁷— or —NR⁷SO₂—. More Preferably, Q is —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —C(S)S—, —C(O)NR⁷— or —OC(O)—. Even more preferably, Q is —O—, —S—, —C(O)— or —C(S)—.

Alternatively, X is a covalent bond, —O—, —S— or —NR⁷—; and R⁴ is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group.

Preferably, R⁴ is an optionally substituted aliphatic, such as a lower alkyl, or aryl group. More preferably, R⁴ is an optionally substituted aryl or lower arylalkyl group. Even more preferably, R⁴ is selected from the group consisting of:

wherein each of rings A-Z5 is optionally and independently substituted; and each x is independently 0 or 1, specifically x is 0. Even more preferably, R⁴ is an optionally substituted

group. Alternatively, R⁴ is an optionally substituted phenyl group. Alternatively, R⁴ is an aryl group substituted with Ar³, such as a phenyl group substituted with Ar³. It is noted that, as shown above, rings A-Z5 can be attached to variable “X” of Structural Formula (I) through —(CH₂)_(x)— at any ring carbon of rings A-Z5 which is not at a position bridging two aryl groups. For example, R⁴ represented by

means that R⁴ is attached to variable “X” through either ring J or ring K.

Preferred substituents for each of the aliphatic group and the aryl group represented by R⁴, including lower alkyl, arylalkyl and rings A-Z5, include halogen, alkyl, haloalkyl, Ar³, Ar³—Ar³, —OR⁵⁰, —O(haloalkyl), —SR⁵⁰, —NO₂, —CN, —NCS, —N(R⁵¹)₂, —NR⁵¹C(O)R⁵⁰, —NR⁵¹C(O)OR⁵², —N(R⁵¹)C(O)N(R⁵¹)₂, —C(O)R⁵⁰, —C(S)R⁵⁰, —C(O)OR⁵⁰, —OC(O)R⁵⁰, —C(O)N(R⁵¹)₂, —S(O)₂R⁵⁰, —SO₂N(R⁵¹)₂, —S(O)R⁵², —SO₃R⁵⁰, —NR⁵¹SO₂N(R⁵¹)₂, —NR⁵¹SO₂R⁵², —V₄—Ar³, —V—OR⁵⁰, —V₄—O(haloalkyl), —V₄—SR⁵⁰, —V₄—NO₂, —V₄—CN, —V₄—N(R⁵¹)₂, —V₄—NR⁵¹C(O)R⁵⁰, —V₄—NR⁵¹CO₂R⁵², —V₄—N(R⁵¹)C(O)N(R⁵¹)₂, —V₄—C(O)R⁵⁰, —V₄—C(S)R⁵⁰, —V₄—CO₂R⁵⁰, —V₄—OC(O)R⁵⁰, —V₄—C(O)N(R⁵¹)₂—, —V₄—S(O)₂R⁵⁰, —V₄—SO₂N(R⁵¹)₂, —V₄—S(O)R⁵², —V₄—SO₃R⁵⁰, —V₄—NR⁵¹SO₂N(R⁵¹)₂, —V₄—NR⁵¹SO₂R⁵², —O—V₄—Ar³, —O—V₅—N(R⁵¹)₂, —S—V₄—Ar³, —S—V₅—N(R⁵¹)₂, —N(R⁵¹)—V₄—Ar³, —N(R⁵¹)—V₅—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—Ar³, —C(O)—V₄—N(R⁵¹)₂, —C(O)—V₄—Ar³, —C(S)—V₄—N(R⁵¹)₂, —C(S)—V₄—Ar³, —C(O)O—V₅—N(R⁵¹)₂, —C(O)O—V₄—Ar³, —O—C(O)—V₅—N(R⁵¹)₂, —O—C(O)—V₄—Ar³, —C(O)N(R⁵¹)—V₅—N(R⁵¹)₂, —C(O)N(R⁵¹)—V₄—Ar³, —S(O)₂—V₄—N(R⁵¹)₂, —S(O)₂—V₄—Ar³, —SO₂N(R⁵¹)—V₅—N(R⁵¹)₂, —SO₂N(R⁵¹)—V₄—Ar³, —S(O)—V₄—N(R⁵¹)₂, —S(O)—V₄—Ar³, —S(O)₂—O—V₅—N(R⁵¹)₂, —S(O)₂—O—V₄—Ar³, —NR⁵¹SO₂—V₄—N(R⁵¹)₂, —NR⁵¹SO₂—V₄—Ar³, —O—[CH₂]_(p′)—O—, —S—[CH₂]_(p′)—S—, and —[CH₂]_(q′)—. More preferably, substituents for each of the aliphatic group and the aryl group represented by R⁴, including lower alkyl, arylalkyl and rings A-Z5, include halogen, C1-C10 alkyl, C1-C10 haloalkyl, Ar³, Ar³—Ar³, —OR⁵⁰, —O(haloalkyl), —SR⁵⁰, —NO₂, —CN, —N(R⁵¹)₂, —NR⁵¹C(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —OC(O)R⁵⁰, —C(O)N(R⁵¹)₂, —V₄—Ar³, —V—OR⁵⁰, —V₄—O(haloalkyl), —V₄—SR⁵⁰, —V₄—NO₂, —V₄—CN, —V₄—N(R⁵¹)₂, —V₄—NR⁵¹C(O)R⁵⁰, —V₄—C(O)R⁵⁰, —V₄—CO₂R⁵⁰, —V₄—OC(O)R⁵⁰, —V₄—C(O)N(R⁵¹)₂—, —O—V₄—Ar³, —O—V₅—N(R⁵¹)₂, —S—V₄—Ar³, —S—V₅—N(R⁵¹)₂, —N(R⁵¹)—V₄—Ar³, —N(R⁵¹)—V₅—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—Ar³, —C(O)—V₄—N(R⁵¹)₂, —C(O)—V₄—Ar³, —C(O)O—V₅—N(R⁵¹)₂, —C(O)O—V₄—Ar³, —O—C(O)—V₅—N(R⁵¹)₂, —O—C(O)—V₄—Ar³, —C(O)N(R⁵¹)—V₅—N(R⁵¹)₂, —C(O)N(R⁵¹)—V₄—Ar³, —O—[CH₂]_(p′)—O— and —[CH₂]_(q′)—. More preferably, substituents for each of the aliphatic group and the aryl group represented by R⁴, including lower alkyl, arylalkyl and rings A-Z5, include halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 diallylamino, aryl, aryloxy, hydroxy, C1-10 alkoxy, —O—[CH₂]_(p)—O— or —[CH₂]_(q)—. Even more preferably, substituents for each of the aliphatic group and the aryl group represented by R⁴, including lower alkyl, arylalkyl and rings A-Z5, include halogen, cyano, amino, nitro, Ar³, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and C1-C6 haloalkoxy. Even more preferably, substituents for each of the aliphatic and aryl groups represented by R⁴, including lower alkyl, arylalkyl and rings A-Z5, include —OH, —OCH₃, —OC₂H₅ and —O—[CH₂]_(p′)—O—. Preferably, phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, —OR⁵⁰, —Ar³, —V₄—Ar³, —V—OR⁵⁰, —O(C1-C10 haloalkyl), —V₄—O(C1-C10 haloalkyl), —O—V₄—Ar³, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—. More preferably, phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, aryl, aryloxy, hydroxy, C1-10 alkoxy, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—. Even more preferably, phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅ and —O—[CH₂]_(p)—O—. Specifically, when R⁴ is phenyl ring A, at least one of the substituents of ring A is at the para position.

R⁵ and R⁶ are each independently —H, —OH, —SH, a halogen, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group, or a substituted or unsubstituted lower aliphatic group. Preferably, R⁵ and R⁶ are each independently —H; —OH; a halogen; or a lower alkoxy or lower alkyl group. More preferably, R⁵ and R⁶ are each independently —H, —OH or a halogen. Even more preferably, R⁵ and R⁶ are each independently —H.

Each R⁷ is independently —H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aryl group, or R⁷ and R⁴ taken together with the nitrogen atom of NR⁷R⁴ form a substituted or unsubstituted non-aromatic heterocyclic group. Preferably, each R⁷ is independently —H, an aliphatic group or phenyl. Even more preferably, each R⁷ is independently —H or C1-C6 alkyl.

Each n is independently 1, 2, 3, 4, 5 or 6. Preferably, each n is independently 1, 2, 3 or 4. Alternatively, each n is independently 2, 3, 4 or 5.

Each p is independently 1, 2, 3 or 4, preferably 1 or 2.

Each q is independently 3, 4, 5 or 6, preferably 3 or 4.

Each p′ is independently 1, 2, 3 or 4, preferably 1 or 2.

Each q′ is independently 3, 4, 5 or 6, preferably 3 or 4.

Each V_(o) is independently a C1-C10 alkylene group, preferably C1-C4 alkylene group.

Each V₁ is independently a C2-C10 alkylene group, specifically C2-C4 alkylene group.

Each V₂ is independently a C1-C4 alkylene group.

Each V₄ is independently a C1-C10 alkylene group, preferably a C1-C4 alkylene group.

Each V₅ is independently a C2-C10 alkylene group, preferably a C2-C4 alkylene group.

Each Ar¹ is an aryl group optionally and independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl. Preferably, Ar¹ is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. More preferably, Ar¹ is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each Ar² is an aryl group optionally and independently substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

Each Ar³ is independently an aryl group, such as phenyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl. Preferably, Ar³ is independently an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C10 alkyl, C1-C10 haloalkyl, hydroxy, C1-C10 alkoxy, nitro, cyano, C1-C10 alkoxycarbonyl, C1-C10 alkylcarbonyl, C1-C10 haloalkoxy, amino, C1-C10 alkylamino and C1-C10 dialkylamino. Even more preferably, Ar³ is independently an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 alkoxy, nitro, cyano, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 haloalkoxy, amino, C1-C4 alkylamino and C1-C4 dialkylamino.

Each R³⁰ is independently hydrogen; an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl and alkylcarbonyl. Preferably, each R³⁰ is independently hydrogen; an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C1 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl. More preferably, each R³⁰ is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C1 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl.

Each R³¹ is independently R³⁰, —CO₂R³⁰, —SO₂R³⁰ or —C(O)R³⁰; or —N(R³¹)₂ taken together is an optionally substituted non-aromatic heterocyclic group. Preferably, each R³¹ is independently R³⁰, or N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group.

Each R³² is independently an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl and alkylcarbonyl. Preferably, each R³² is independently an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C1 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl. More preferably, each R³² is independently a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C1 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl.

Each R⁴⁰ is independently hydrogen; an aryl group, such as a phenyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

Each R⁴¹ is independently R⁴⁰, —CO₂R⁴⁰, —SO₂R⁴⁰ or —C(O)R⁴⁰; or —N(R⁴¹)₂ taken together is an optionally substituted non-aromatic heterocyclic group.

Each R⁴² is independently an aryl group, such as a phenyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

Each R⁵⁰ is independently hydrogen; an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl. Preferably, each R⁵⁰ is independently hydrogen; an aryl group, such as a phenyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

Each R⁵¹ is independently R⁵⁰, —CO₂R⁵⁰, —SO₂R⁵⁰ or —C(O)R⁵⁰, or —N(R⁵¹)₂ taken together is an optionally substituted non-aromatic heterocyclic group. Preferably, each R⁵¹ is independently R⁵⁰, or —N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group.

Each R⁵² is independently an aryl group optionally substituted with one or two substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl. Preferably, each R⁵² is independently an aryl group, such as a phenyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

R and R′ are each independently —H; a lower aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO₂, —NH₂, lower alkoxy, lower haloalkoxy and aryl; or an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO₂, —NH₂, lower alkoxy, lower haloalkoxy, lower aliphatic group and lower haloaliphatic group; or R and R′ taken together with the nitrogen atom of NRR′ form a non-aromatic heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of: halogen; —OH; —CN; —NCS; —NO₂; —NH₂; lower alkoxy; lower haloalkoxy; lower aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO₂, —NH₂, lower alkoxy, lower haloalkoxy and aryl; and aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO₂, —NH₂, lower alkoxy, lower haloalkoxy, lower aliphatic group and lower haloaliphatic group. Preferably, R and R′ are each independently —H; a lower aliphatic group; a lower aliphatic group substituted with phenyl; or an aryl group. More preferably, R and R′ are each independently —H, C1-C4 alkyl, phenyl or benzyl.

A second set of values for the variables in Structural Formula (I) is provided in the following paragraphs:

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

R¹ is an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar¹, —OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰, —NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰, —NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_(o)—Ar¹, —V_(o)—OR³⁰, —V_(o)—O(haloalkyl), —V_(o)—SR³⁰, —V_(o)—NO₂, —V_(o)—CN, —V_(o)—N(R³¹)₂, —V_(o)—NR³¹C(O)R³⁰, —V_(o)—NR³¹CO₂R³², —V_(o)—N(R³¹)C(O)N(R³¹)₂, —V_(o)—C(O)R³⁰, —V_(o)—C(S)R³⁰, —V_(o)—CO₂R³⁰, —V_(o)—OC(O)R³⁰, —V_(o)—C(O)N(R³¹)₂—, —V_(o)—S(O)₂R³⁰, —V_(o)—SO₂N(R³¹)₂, —V_(o)—S(O)R³², —V_(o)—SO₃R³⁰, —V_(o)—NR³¹SO₂N(R³¹)₂, —V_(o)—NR³¹SO₂R³², —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_(o)—N(R³¹)₂, —NR³¹C(O)—V_(o)—Ar¹, —C(O)—V_(o)—N(R³¹)₂, —C(O)—V_(o)—Ar¹, —C(S)—V_(o)—N(R³¹)₂, —C(S)—V_(o)—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_(o)—Ar¹, —O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_(o)—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂, —C(O)N(R³¹)—V_(o)—Ar¹, —S(O)₂—V_(o)—N(R³¹)₂, —S(O)₂—V_(o)—Ar¹, —SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_(o)—Ar¹, —S(O)—V_(o)—N(R³¹)₂, —S(O)—V_(o)—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_(o)—Ar¹, —NR³¹SO₂—V_(o)—N(R³¹)₂, —NR³¹SO₂—V_(o)—Ar¹, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S— and —[CH₂]_(q)—.

Values and preferred values for the remainder of the variables of Structural Formula (I) are each independently as described above for the first set of values.

A third set of values for the variables in Structural Formula (I) is provided in the following four paragraphs.

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

R¹ is an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar¹, —OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰, —NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰, —NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_(o)—Ar¹, —V_(o)—OR³⁰, —V_(o)—O(haloalkyl), —V_(o)—SR³⁰, —V_(o)—NO₂, —V_(o)—CN, —V_(o)—N(R³¹)₂, —V_(o)—NR³¹C(O)R³⁰, —V_(o)—NR³¹CO₂R³², —V_(o)—N(R³¹)C(O)N(R³¹)₂, —V_(o)—C(O)R³⁰, —V_(o)—C(S)R³⁰, —V_(o)—CO₂R³⁰, —V_(o)—OC(O)R³⁰, —V_(o)—C(O)N(R³¹)₂—, —V_(o)—S(O)₂R³⁰, —V_(o)—SO₂N(R³¹)₂, —V_(o)—S(O)R³², —V_(o)—SO₃R³⁰, —V_(o)—NR³¹SO₂N(R³¹)₂, —V_(o)—NR³¹SO₂R³², —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_(o)—N(R³¹)₂, —NR³¹C(O)—V_(o)—Ar¹, —C(O)—V_(o)—N(R³¹)₂, —C(O)—V_(o)—Ar¹, —C(S)—V_(o)—N(R³¹)₂, —C(S)—V_(o)—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_(o)—Ar¹, —O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_(o)—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂, —C(O)N(R³¹)—V_(o)—Ar¹, —S(O)₂—V_(o)—N(R³¹)₂, —S(O)₂—V_(o)—Ar¹, —SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_(o)—Ar¹, —S(O)—V_(o)—N(R³¹)₂, —S(O)—V_(o)—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_(o)—Ar¹, —NR³¹SO₂—V_(o)—N(R³¹)₂, —NR³¹SO₂—V_(o)—Ar¹, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S— and —[CH₂]_(q)—.

R² and R³ taken together with the nitrogen atom of —N(R²R³) form a substituted or unsubstituted non-aromatic heterocyclic ring, or a substituted or unsubstituted bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms. Preferably, R² and R³ taken together with the nitrogen atom of —N(R²R³) form a 5- or 6-membered, optionally-substituted non-aromatic heterocyclic ring; or, R² and R³ taken together with the nitrogen atom of —N(R²R³) form a substituted or unsubstituted bridged heterobicyclic ring comprising 6 or 7 ring carbon atoms and 1 or 2 ring nitrogen atoms. More preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group,

Even more preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl, piperidinyl, azepinyl group,

Even more preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl group,

Examples of suitable substituents for the non-aromatic heterocyclic ring or the bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms represented by —NR²R³ are as described in the first set of values for Structural Formula (I).

Values and preferred values for the remainder of the variables of Structural Formula (I) are as described above for the first set of values.

A fourth set of values for the variables in Structural Formula (I) is provided in the following paragraphs:

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

R¹ is an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar¹, —OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰, —NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰, —NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_(o)—Ar¹, —V_(o)—OR³⁰, —V_(o)—O(haloalkyl), —V_(o)—SR³⁰, —V_(o)—NO₂, —V_(o)—CN, —V_(o)—N(R³¹)₂, —V_(o)—NR³¹C(O)R³⁰, —V_(o)—NR³¹CO₂R³², —V_(o)—N(R³¹)C(O)N(R³¹)₂, —V_(o)—C(O)R³⁰, —V_(o)—C(S)R³⁰, —V_(o)—CO₂R³⁰, —V_(o)—OC(O)R³⁰, —V_(o)—C(O)N(R³¹)₂—, —V_(o)—S(O)₂R³⁰, —V_(o)—SO₂N(R³¹)₂, —V_(o)—S(O)R³², —V_(o)—SO₃R³⁰, —V_(o)—NR³¹SO₂N(R³¹)₂, —V_(o)—NR³¹SO₂R³², —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_(o)—N(R³¹)₂, —NR³¹C(O)—V_(o)—Ar¹, —C(O)—V_(o)—N(R³¹)₂, —C(O)—V_(o)—Ar¹, —C(S)—V_(o)—N(R³¹)₂, —C(S)—V_(o)—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_(o)—Ar¹, —O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_(o)—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂, —C(O)N(R³¹)—V_(o)—Ar¹, —S(O)₂—V_(o)—N(R³¹)₂, —S(O)₂—V_(o)—Ar¹, —SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_(o)—Ar¹, —S(O)—V_(o)—N(R³¹)₂, —S(O)—V_(o)—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_(o)—Ar¹, —NR³¹SO₂—V_(o)—N(R³¹)₂, —NR³¹SO₂—V_(o)—Ar¹, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S— and —[CH₂]_(q)—.

R² and R³ taken together with the nitrogen atom of —N(R²R³) form a substituted or unsubstituted non-aromatic heterocyclic ring, or a substituted or unsubstituted bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms. Preferably, R² and R³ taken together with the nitrogen atom of —N(R²R³) form a 5- or 6-membered, optionally-substituted non-aromatic heterocyclic ring; or, R² and R³ taken together with the nitrogen atom of —N(R²R³) form a substituted or unsubstituted bridged heterobicyclic ring comprising 6 or 7 ring carbon atoms and 1 or 2 ring nitrogen atoms. More preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group

Even more preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl, piperidinyl, azepinyl group,

Even more preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl group,

Examples of suitable substituents for the non-aromatic heterocyclic ring or the bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms represented by —NR²R³ are as described in the first set of values for Structural Formula (I).

R⁵ and R⁶ are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

Values and preferred values of the remainder of the variables of Structural Formula (I) are each independently as described above for the first set of values.

A fifth set of values for the variables in Structural Formula (I) is provided in the following paragraphs:

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

R¹ is an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar¹, —OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰, —NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰, —NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_(o)—Ar¹, —V_(o)—OR³⁰, —V_(o)—O(haloalkyl), —V_(o)—SR³⁰, —V_(o)—NO₂, —V_(o)—CN, —V_(o)—N(R³¹)₂, —V_(o)—NR³¹C(O)R³⁰, —V_(o)—NR³¹CO₂R³², —V_(o)—N(R³¹)C(O)N(R³¹)₂, —V_(o)—C(O)R³⁰, —V_(o)—C(S)R³⁰, —V_(o)—CO₂R³⁰, —V_(o)—OC(O)R³⁰, —V_(o)—C(O)N(R³¹)₂—, —V_(o)—S(O)₂R³⁰, —V_(o)—SO₂N(R³¹)₂, —V_(o)—S(O)R³², —V_(o)—SO₃R³⁰, —V_(o)—NR³¹SO₂N(R³¹)₂, —V_(o)—NR³¹SO₂R³², —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_(o)—N(R³¹)₂, —NR³¹C(O)—V_(o)—Ar¹, —C(O)—V_(o)—N(R³¹)₂, —C(O)—V_(o)—Ar¹, —C(S)—V_(o)—N(R³¹)₂, —C(S)—V_(o)—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_(o)—Ar¹, —O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_(o)—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂, —C(O)N(R³¹)—V_(o)—Ar¹, —S(O)₂—V_(o)—N(R³¹)₂, —S(O)₂—V_(o)—Ar¹, —SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_(o)—Ar¹, —S(O)—V_(o)—N(R³¹)₂, —S(O)—V_(o)—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_(o)—Ar¹, —NR³¹SO₂—V_(o)—N(R³¹)₂, —NR³¹SO₂—V_(o)—Ar¹, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S— and —[CH₂]_(q)—.

R² and R³ taken together with the nitrogen atom of —N(R²R³) form a substituted or unsubstituted non-aromatic heterocyclic ring, or a substituted or unsubstituted bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms. Preferably, R² and R³ taken together with the nitrogen atom of —N(R²R³) form a 5- or 6-membered, optionally-substituted non-aromatic heterocyclic ring; or, R² and R³ taken together with the nitrogen atom of —N(R²R³) form a substituted or unsubstituted bridged heterobicyclic ring comprising 6 or 7 ring carbon atoms and 1 or 2 ring nitrogen atoms, More preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group,

Even more preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl, piperidinyl, azepinyl group,

Even more preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl group,

Examples of suitable substituents for the non-aromatic heterocyclic ring or the bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms represented by —NR²R³ are as described in the first set of values for Structural Formula (I).

R⁴ is an aliphatic or aryl group each optionally substituted with one or more substituents. Examples of suitable substituents are as described above for the first set of values.

R⁵ and R⁶ are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

Values and preferred values of the remainder of the variables of Structural Formula (I) are each independently as described above for the first set of values.

In a second embodiment, the glucosylceramide synthase inhibitor is represented by Structural Formula (II), (III), (IV), (V), (VI), (VII) or (VIII):

or a pharmaceutically acceptable salt thereof.

A first set of values for the variables of Structural Formulas (II)-(VIII) is provided in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —NR³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S— and —[CH₂]_(q)—. Preferably, R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—.

Ar¹ is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, Ar¹ is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

R³⁰ is independently hydrogen; an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, R³⁰ is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group. Examples of suitable substituents are as described above in the first set of values for Structural Formula (I).

R² and R³ taken together with the nitrogen atom of —N(R²R³) form a substituted or unsubstituted non-aromatic heterocyclic ring, or a substituted or unsubstituted bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms. Preferably, R² and R³ taken together with the nitrogen atom of —N(R²R³) form a 5- or 6-membered, optionally-substituted non-aromatic heterocyclic ring; or, R² and R³ taken together with the nitrogen atom of —N(R²R³) form a substituted or unsubstituted bridged heterobicyclic ring comprising 6 or 7 ring carbon atoms and 1 or 2 ring nitrogen atoms. More preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group,

Even more preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl, piperidinyl, azepinyl group,

Even more preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl group,

Examples of suitable substituents for the non-aromatic heterocyclic ring or the bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms represented by —NR²R³ are as described in the first set of values for Structural Formula (I).

R⁴ is an aliphatic or aryl group each optionally substituted with one or more substituents described above in the first set of values for Structural Formula (I).

R⁵ and R⁶ for Structural Formulas (II), (III) and (V) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

For Structural Formula (VIII), R⁷ is —H or C1-C6 alkyl, preferably —H.

Values and preferred values of the remainder of the variables of Structural Formulas (II)-(VIII) are each independently as described above in the first set of values for Structural Formula (I).

A second set of values for the variables in Structural Formulas (II)-(VIII) is provided in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or —[CH₂]_(q)—. Preferably, R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—.

Ar¹ is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, Ar¹ is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

R³⁰ is independently hydrogen; an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, R³⁰ is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group or

each optionally substituted at one or more ring carbon atoms with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Preferably, —N(R²R³) is a pyrrolidinyl, piperidinyl, or azepinyl group, or

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. More preferably, —N(R²R³) is pyrrolidinyl,

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

R⁴ is an aliphatic or aryl group each optionally substituted with one or more substituents. Examples of suitable substituents are described above in the first set of values for Structural Formula (I).

R⁵ and R⁶ for Structural Formulas (II), (III) and (V) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

For Structural Formula (VIII), R⁷ is —H or C1-C6 alkyl, preferably —H.

Values and preferred values of the remainder of the variables of Structural Formulas (II)-(VIII) are each independently as described above in the first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formulas (II)-(VIII) is provided in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or —[CH₂]_(q)—. Preferably, R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—.

Ar¹ is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, Ar¹ is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

R³⁰ is independently hydrogen; an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, R³⁰ is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group or

each optionally substituted at one or more ring carbon atoms with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Preferably, —N(R²R³) is a pyrrolidinyl, piperidinyl, or azepinyl group, or

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. More preferably, —N(R²R³) is pyrrolidinyl,

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

R⁴ is an optionally substituted aryl or an optionally substituted lower arylalkyl group. Example of suitable substituents are as described in the first set of values for Structural Formula (I).

R⁵ and R⁶ for Structural Formulas (II), (III) and (V) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

For Structural Formula (VIII), R⁷ is —H.

Preferably, Q in Structural Formula (II) is —O—, —S—, —C(O)—, —C(S)—, —NR⁷(CO)— or —C(O)NR⁷—

Values and preferred values of the remainder of the variables of Structural Formulas (II)-(VIII) are each independently as described above in the first set of values for Structural Formula (I). Preferably, for Structural Formula (II), Q is —O—, —S—, —C(O)—, —C(S)—, —NR⁷(CO)— or —C(O)NR⁷—.

A fourth set of values for the variables in Structural Formulas (II)-(VIII) is provided in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or —[CH₂]_(q)—. Preferably, R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—.

Ar¹ is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³⁰ is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group or

each optionally substituted at one or more ring carbon atoms with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Preferably, —N(R²R³) is a pyrrolidinyl, piperidinyl, or azepinyl group, or

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. More preferably, —N(R²R³) is pyrrolidinyl,

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

R⁴ is an optionally substituted aryl or an optionally substituted lower arylalkyl group. Examples of suitable substitutents for R⁴ are as provided above in the first set of values for Structural Formula (I). Preferably, R⁴ is selected from the group consisting of:

Each of rings A-Z5 is optionally and independently substituted.

For Structural Formula (VIII), R⁷ is —H.

Values and preferred values of the remainder of the variables of Structural Formulas (II)-(VIII) are each independently as described above in the first set of values for Structural Formula (I). When the compound of the invention is represented by Structural Formula (III) or (IV), or a pharmaceutically acceptable salt thereof, n is 1, 2, 3 or 4. Alternatively, when the compound of the invention is represented by Structural Formula (V) or (VI), or a pharmaceutically acceptable salt thereof, n is 3, 4 or 5.

A fifth set of values for the variables in Structural Formulas (II)-(VIII) independently is as defined in the first set, second set, third set, fourth set, fifth set, sixth set or seventh set of values for the variables for Structural Formula (I).

In a third embodiment, the compound of the invention is represented by Structural Formula (IX) or (X):

or a pharmaceutically acceptable salt thereof.

A first set of values for the variables in Structural Formulas (IX) and (X) is defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or more substituents. Examples of suitable substituents include halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)₂—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, and —[CH₂]_(q)—; preferably, R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅ and —O—[CH₂]_(p)—O—.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group or

each optionally substituted at one or more ring carbon atoms with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Preferably, —N(R²R³) is a pyrrolidinyl, piperidinyl, or azepinyl group, or

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. More preferably, —N(R²R³) is pyrrolidinyl,

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

Phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, —OR⁵⁰, —Ar³, —V₄—Ar³, —V—OR⁵⁰, —O(C1-C10 haloalkyl), —V₄—O(C1-C10 haloalkyl), —O—V₄—Ar³, —O—[CH₂]_(p′)—O— and —[CH₂]_(q′)—.

Ar³ is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R⁵⁰ is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

For Structural Formula (IX), n is 1, 2, 3 or 4. For Structural Formula (X), n is 3, 4 or 5.

Values and preferred values of the remainder of the variables of Structural Formulas (IX) and (X) are each independently as defined above in the first set of values for Structural Formula (I).

A second set of values and preferred values for the variables in Structural Formulas (IX) and (X) is as defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkoxy(C1-C6)alkoxy, C1-C6 haloalkoxy(C1-C6)alkoxy, C1-C6 hydroxyalkoxy and —O—[CH₂]_(p)—O—.

—N(R²R³) is pyrrolidinyl,

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

Phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, aryl, aryloxy, hydroxy, C1-C10 alkoxy, —O—[CH₂]_(p′)—O— and —[CH₂]_(q′)—. Preferably, phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅ and —O—[CH₂]_(p′)—O—.

For Structural Formula (IX), n is 1, 2, 3 or 4. For Structural Formula (X), n is 3, 4 or 5.

Values and preferred values of the remaining variables of Structural Formulas (IX) and (X) are each independently as described above in the first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formulas (IX) and (X) independently is as defined in the first set, second set, third set, fourth set or fifth set, of values for Structural Formulas (II)-(VIII).

In a fourth embodiment, the compound of the invention is represented by Structural Formula (XI), (XII) or (XIII):

or a pharmaceutically acceptable salt thereof.

A first set of values and preferred values for the variables of Structural Formulas (XI)-(XIII) is defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or —[CH₂]_(q)—. Preferably, R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—.

Ar¹ is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, Ar¹ is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

R³⁰ is independently hydrogen; an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, R³⁰ is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group. Examples of suitable substituents are as described above in the first set of values for Structural Formula (I).

R² and R³ taken together with the nitrogen atom of —N(R²R³) form a substituted or unsubstituted non-aromatic heterocyclic ring, or a substituted or unsubstituted bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms. Preferably, R² and R³ taken together with the nitrogen atom of —N(R²R³) form a 5- or 6-membered, optionally-substituted non-aromatic heterocyclic ring; or, R² and R³ taken together with the nitrogen atom of —N(R²R³) form a substituted or unsubstituted bridged heterobicyclic ring comprising 6 or 7 ring carbon atoms and 1 or 2 ring nitrogen atoms. More preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group,

Even more preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl, piperidinyl, azepinyl group,

Even more preferably, —N(R²R³) is a substituted or unsubstituted pyrrolidinyl group,

Examples of suitable substituents for the non-aromatic heterocyclic ring or the bridged heterobicyclic ring comprising 6-10 ring carbon atoms and 1 or 2 ring nitrogen atoms represented by —NR²R³ are as described in the first set of values for Structural Formula (I).

R⁴ is an optionally substituted aryl group. Examples of suitable substituents for R⁴ are as provided above in the first set of values for Structural Formula (I).

Alternatively, R⁴ is a straight chained C1-C20 alkyl group, preferably C6-C20 alkyl group, more preferably C6-C10 alkyl group, even more preferably C6-C8 alkyl group, each optionally substituted with hydroxy.

R⁵ and R⁶ for Structural Formula (XI) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

Values and preferred values of the remainder of the variables of Structural Formulas (XI)-(XIII) are each independently as described above in the first set of values for Structural Formula (I).

A second set of values and preferred values for the variables of Structural Formulas (XI)-(XIII) is defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or —[CH₂]_(q)—. Preferably, R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂], —O—, and —[CH₂]_(q)—.

Ar¹ is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³⁰ is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group or

each optionally substituted at one or more ring carbon atoms with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Preferably, —N(R²R³) is a pyrrolidinyl, piperidinyl, or azepinyl group, or

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. More preferably, —N(R²R³) is pyrrolidinyl,

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

R⁴ is an optionally substituted aryl group. Suitable substituents and preferred substitutents are as provided above in the first set of values for Structural Formula (I). Preferably, R⁴ is selected from the group consisting of:

Each of rings A-Z5 is optionally and independently substituted. Preferably, each of rings A-Z5 is optionally and independently substituted with one or more substituents selected from Ar³ and Ar³—Ar³ wherein values and preferred values of Ar³ are as described above for the first set of values for Structural Formula (I). Preferably, Ar³ is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C10 alkyl, C1-C10 haloalkyl, hydroxy, C1-C10 alkoxy, nitro, cyano, C1-C10 alkoxycarbonyl, C1-C10 alkylcarbonyl, C1-C10 haloalkoxy, amino, C1-C10 alkylamino and C1-C10 dialkylamino. More preferably, Ar³ is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 alkoxy, nitro, cyano, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 haloalkoxy, amino, C1-C4 alkylamino and C1-C4 dialkylamino.

Alternatively, R⁴ is a straight chained C1-C20 alkyl group optionally substituted with hydroxy, preferably a straight chained C6-C20 alkyl group, more preferably a straight chained C6-C10 alkyl group, even more preferably a straight chained C6-C8 alkyl group.

R⁵ and R⁶ for Structural Formula (XI) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

Values and preferred values of the remainder of the variables of Structural Formulas (XI)-(XIII) are each independently as described above in the first set of values for Structural Formula (I).

A third set of values for the variables of Structural Formulas (XI)-(XIII) is defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or —[CH₂]_(q)—. Preferably, R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O—, and —[CH₂]_(q)—.

Ar¹ is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³⁰ is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group.

—N(R²R³) is a pyrrolidinyl, piperidinyl, or azepinyl group, or

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. Preferably, —N(R²R³) is pyrrolidinyl,

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

R⁴ is a biaryl group, such as a biphenyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, nitro, Ar³, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and C1-C6 haloalkoxy.

Alternatively, R⁴ is a straight chained C1-C20 alkyl group optionally substituted with hydroxy, preferably a straight chained C6-C20 alkyl group, more preferably a straight chained C6-C10 alkyl group, even more preferably a straight chained C6-C8 alkyl group.

R⁵ and R⁶ for Structural Formula (XI) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group, preferably —H.

Values and preferred values of the remainder of the variables of Structural Formulas (XI)-(XIII) are each independently as described above in the first set of values for Structural Formula (I).

A fourth set of values for the variables of Structural Formulas (XI)-(XIII) is defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkoxy(C1-C6)alkoxy, C1-C6 haloalkoxy(C1-C6)alkoxy, C1-C6 hydroxyalkoxy and —O—[CH₂]_(p)—O—. Preferably, R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅ and —O—[CH₂]_(p)—O—. Alternatively, R¹ is

where r is 1, 2, 3 or 4, preferably 1 or 2.

—N(R²R³) is pyrrolidinyl,

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

R⁴ is a biaryl group, such as a biphenyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, nitro, Ar³, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and C1-C6 haloalkoxy.

Alternatively, R⁴ is a straight chained C1-C20 alkyl group optionally substituted with hydroxy, preferably a straight chained C6-C20 alkyl group, more preferably a straight chained C6-C10 alkyl group, even more preferably a straight chained C6-C8 alkyl group.

R⁵ and R⁶ for Structural Formula (XI) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group, preferably —H.

n is an integer from 1 to 4.

Values and preferred values of the remainder of the variables of Structural Formulas (XI)-(XIII) are each independently as described above in the first set of values for Structural Formula (I).

A fifth set of values preferred values for the variables of Structural Formulas (XI)-(XIII) is defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkoxy(C1-C6)alkoxy, C1-C6 haloalkoxy(C1-C6)alkoxy, C1-C6 hydroxyalkoxy and —O—[CH₂]_(p)—O—. Alternatively, R¹ is

where r is 1, 2, 3 or 4, preferably 1 or 2.

—N(R²R³) is pyrrolidinyl,

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

R⁴ is

optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, nitro, Ar³, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and C1-C6 haloalkoxy.

Alternatively, R⁴ is a straight chained C6-C8 alkyl group.

n is 1.

R⁵ and R⁶ for Structural Formula (XI) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group, preferably —H.

Values and preferred values of the remainder of the variables of Structural Formulas (XI)-(XIII) are each independently as described above in the first set of values for Structural Formula (I).

A sixth set of values for the variables in Structural Formulas (XI)-(XIII) independently is as defined in the first set, second set, third set, fourth set, fifth set, sixth set or seventh set of values for Structural Formula (I).

In a fifth embodiment, the compound of the invention is represented by Structural Formula (XIV) or (XV):

or a pharmaceutically acceptable salt thereof. A first set of values and preferred values for the variables in Structural Formulas (XIV) and (XV) is as defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, or —[CH₂]_(q)—. Preferably, R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O—, and —[CH₂]_(q)—.

Ar¹ is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy and C1-C6 haloalkyl.

Each R³⁰ is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group or

each optionally substituted at one or more ring carbon atoms with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Preferably, —N(R²R³) is a pyrrolidinyl, piperidinyl, or azepinyl group, or

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. More preferably, —N(R²R³) is pyrrolidinyl,

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

k is 0, 1, 2, 3, 4, 5 or 6.

R⁸ is —H, or an optionally substituted aryl or an optionally substituted lower alkyl group. Examples of suitable substituents are as described for the first set of values for Structural Formula (I). Preferably, R⁸ is selected from the group consisting of:

Each of rings A-Z5 is optionally and independently substituted. Examples of suitable substituents for R⁸ are as provided above in the first set of values for R⁴ in Structural Formula (I). More preferably, R⁸ is a

group. Alternatively, R⁸ is an aryl group substituted with Ar³, such as a phenyl group substituted with Ar³, where values and preferred values of Ar³ are as described above in Structural Formula (I).

Values and preferred values of the remainder of the variables of Structural Formulas (XIV) and (XV) are each independently as described above in the first set of values for Structural Formula (I).

A second set of values for the variables in Structural Formulas (XIV) and (XV) is defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V—OR³⁰, —V—N(R³¹)₂, —V—Ar¹, —O—V—Ar¹, —O—V₁—N(R³¹)₂, —S—V—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S— and —[CH₂]_(q)—.

Ar¹ is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³⁰ is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6-alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, azepinyl or morpholinyl group or

each optionally substituted at one or more ring carbon atoms with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl or C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Preferably, —N(R²R³) is a pyrrolidinyl, piperidinyl, or azepinyl group, or

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. More preferably, —N(R²R³) is pyrrolidinyl,

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

Values and preferred values for k and R⁸ are as provided above in the first set of values for Structural Formulas (XIV) and (XV).

Values and preferred values of the remainder of the variables of Structural Formulas (XIV) and (XV) are each independently as described above in the first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formulas (XIV) and (XV) is defined in the following paragraphs:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkoxy(C1-C6)alkoxy, C1-C6 haloalkoxy(C1-C6)alkoxy, C1-C6 hydroxyalkoxy and —O—[CH₂]_(p)—O—. Preferably, R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅ and —O—[CH₂]_(p)—O—. Alternatively, R¹ is

where r is 1, 2, 3 or 4, preferably 1 or 2.

—N(R²R³) is pyrrolidinyl,

each optionally substituted at one or more ring carbon atoms with halogen, —OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

Values and preferred values for k and R⁸ are each independently as provided above in the first set of values for Structural Formulas (XIV) and (XV).

Values and preferred values of the remainder of the variables of Structural Formulas (XIV) and (XV) are each independently as described above in the first set of values for Structural Formula (I).

A fourth set of values for the variables in Structural Formulas (XIV)-(XV) is as defined in the first set, second set, third set, fourth set, fifth set, sixth set or seventh set for Structural Formula (I).

In one preferred embodiment, the compound of the invention is represented by Structural Formula (XVIA) or (XVIB):

or a pharmaceutically acceptable salt thereof, wherein: Q is —O—, —C(O)— or —NH, specifically, —O— or —C(O)—; r and s are each independently 1, 2, 3 or 4; each n independently is 1, 2, 3, 4, 5 or 6; and R⁴ has values and preferred values provided above in the first set of values for Structural Formula (I).

In an alternative, —O—(CH₂)r-O— is replaced by one or more substituents selected from the group consisting of —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkoxy(C1-C6)alkoxy, C1-C6 haloalkoxy(C1-C6)alkoxy, C1-C6 hydroxyalkoxy and —O—[CH₂]_(p)—O—, preferably by one or more substituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅ and —O—[CH₂]_(p)—O—, and/or R4 is a straight chained C6-C8 alkyl group.

In another preferred embodiment, the compound of the invention is represented by Structural Formula (XVIC) or (XVID):

or a pharmaceutically acceptable salt thereof, wherein:

Q is —O—, —C(O)— or —NH, specifically, —O— or —C(O)—;

r and s are each independently 1, 2, 3 or 4;

each n independently is 1, 2, 3, 4, 5 or 6;

R⁴ has values and preferred values provided above in the first set of values for Structural Formula (I). Alternatively, —(CH₂)n-R⁴ is a C6-C8 straight chained alkyl group, optionally substituted with hydroxy, and/or —O—(CH₂)r-O— is replaced by one or more substituents selected from the group consisting of —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkoxy(C1-C6)alkoxy, C1-C6 haloalkoxy(C1-C6)alkoxy, C1-C6 hydroxyalkoxy and —O—[CH₂]_(p)—O—, preferably by one or more substituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅ and —O—[CH₂]_(p)—O—.

B is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. Preferably, B is halogen, hydroxy, C1-C5 alkoxy or C1-C5 haloalkoxy.

k″ is 0 or 1.

In another preferred embodiment, the compound of the invention is represented by Structural Formula (XVII), (XVIII), (XIX) or (XX):

or a pharmaceutically acceptable salt thereof, wherein phenyl ring A is optionally substituted; each n is 1, 2, 3, 4, 5, or 6; and k is 0, 1 or 2. Values and preferred values of suitable substituents of phenyl ring A are as described above in the first set of values for Structural Formula (I).

Examples of bridged heterobicyclic ring comprising 5-12 ring carbon atoms and 1 or 2 ring nitrogen atoms include

The bridged bicyclic ring carbon atoms can be optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, —OH, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl), —O(C1-C6 haloalkyl), —S(C1-C6 haloalkyl), C1-C6 alkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Alternatively, the bridged bicyclic ring carbon atoms can be optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —O(C1-C6 alkyl) and —O(C1-C6 haloalkyl). The bridged bicyclic ring nitrogen atoms can be optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl and phenyl, the alkyl being optionally substituted with halogen, cyano, intro, —OH, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl), —O(C1-C6 haloalkyl), —S(C1-C6 haloalkyl), phenyl, amino, C1-C6 alkylamino and C1-C6 dialkylamino, and the phenyl being optionally substituted with halogen, cyano, nitro, —OH, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl), —O(C1-C6 haloalkyl), —S(C1-C6 haloalkyl), C1-C6 alkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Alternatively, the bridged bicyclic ring nitrogen atoms can be optionally substituted with C1-C6 alkyl that is optionally substituted with halogen, —OH, —O(C1-C6 alkyl) and —O(C1-C6 haloalkyl).

In another embodiment, the compound of the invention is represented by a structural formula selected from Structural Formulas (I)-(VIII) and (XI)-(XV), wherein values, including preferred values, of the variables in the structural formulas, other than R³⁰, R³¹ and R³² for the substituents of R¹, are independently as defined in each embodiment described above for Structural Formulas (I)-(VIII) and (XI)-(XV). In this embodiment, each R³⁰ is independently: i) hydrogen; ii) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, phenyl, phenylamino, diphenylamino, aryloxy, benzoyl, phenoxycarbonyl, alkylamino, dialkylamino, alkoxy, alkoxycarbonyl and alkylcarbonyl. Each R³¹ is independently R³⁰, —CO₂R³⁰, —SO₂R³⁰ or —C(O)R³⁰; or —N(R³¹)₂ taken together is an optionally substituted non-aromatic heterocyclic group. Each R³² is independently: i) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkylcarbonyl and haloalkoxy and haloalkyl; or ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, phenyl, phenylamino, diphenylamino, aryloxy, benzoyl, phenoxycarbonyl, alkylamino, dialkylamino, alkoxy, alkoxycarbonyl and alkylcarbonyl. Each of the phenyl, phenylamino, diphenylamino, aryloxy, benzoyl, phenoxycarbonyl for the substituents of the alkyl group represented by R³⁰ and R³² is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy, C1-C5 haloalkoxy, C1-C5 alkylamino, C1-C5 dialkylamino, (C1-C5 alkoxy)carbonyl and C1-C5 alkyl)carbonyl. Each of the alkylamino, dialkylamino, alkoxy, alkoxycarbonyl and alkylcarbonyl for the substituents of the alkyl group represented by R³⁰ and R³² is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, phenyl, C1-C5 alkoxy, C1-C5 haloalkoxy, phenylamino, C1-C5 alkylamino, C1-C5 dialkylamino, diphenylamino, (C1-C5 alkoxy)carbonyl, C1-C5 alkyl)carbonyl, benzoyl and phenoxycarbonyl.

Another class of glucosylceramide synthase inhibitors include iminosugars and their derivatives. Iminosugars (deoxynojirimycin and its analogs) are polyhydroxylated alkaloids that are structural mimics of monosaccharides, where a nitrogen atom replaces the ring oxygen. Examples of iminosugars and their derivatives have been described, for example:

U.S. Pat. No. 4,065,562, the entire teachings of which are incorporated herein by reference, discloses deoxyjirimycin (2-hydroxymethyl-3,4,5-trihydroxypiperidine);

U.S. Pat. No. 4,182,767, the entire teachings of which are incorporated herein by reference, discloses the following deoxyjirimycin analog:

R is alkyl of 1 to 4 carbon atoms;

U.S. Pat. No. 4,533,668, the entire teachings of which are incorporated herein by reference, discloses the following deoxynojirimycin analog:

wherein X is divalent alkyl or alkenyl of 3 to 6 carbon atoms, Y is hydrogen, methyl or

and Z is

or thienyl, wherein R₁, R₂, R₃ and R₄ are independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl, trihalomethyl, phenoxy, diloweralkylamino, cyano, carboxyl, carbamoyl or carboloweralkoxy, R₅ is hydrogen or hydroxymethyl and R₆ is hydrogen, methyl, ethyl or methoxyethyl, or a pharmaceutically acceptable nontoxic acid addition salt thereof;

U.S. Pat. No. 4,639,436, the entire teachings of which are incorporated herein by reference, discloses the following deoxyjirimycin analog:

wherein R₁ is C₅-C₃₀ alkyl, C₂-C₁₈ alkenyl, C₂-C₁₃ alkinyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C₃-C₈-cycloalkinyl, phenyl (a), C₁-C₂ and C₇-C₃₀ alkyl substituted by phenyl (b) or substituted C₁-C₄-alkyl said C₅-C₃₀ alkyl, cycloalkyl, cycloalkenyl and cycloalkinyl being unsubstituted or substituted by hydroxy, C₁-C₄-alkoxy, acyloxy, amino, mono-C₁-C₄ alkylamino, di-C₁-C₄ alkylamino, acylamino, mercapto, C₁-C₄ alkylthio, halogen, C₁-C₄ alkylcarbonyl, carboxyl nitro, cyano, formyl, sulfo, a heterocyclic radical derived from a hexose or pentose, attached to the alkyl moiety directly via a ring atom or via an —O—, —S— or —NH-bridge or naphthyl said phenyl (a) being unsubstituted or substituted by C₁ to C₁₀ alkyl, C₁ to C₁₀ chloroalkyl, C₁ to C₁₀ nitroalkyl, C₁ to C₁₀ cyanoalkyl, C₁ to C₁₀ alkenyl, hydroxyl, C₁ to C₄ alkoxy, amino, mono-C₁ to C₄ alkylamino, di-C₁-C₄ alkylamino, mercapto, C₁-C₄ alkylthio, carboxyl, C₁-C₄ carbalkoxy, sulfo, C₁-C₄ alkylsulfonyl, phenylsulfonyl, aminosulfonyl, C₁-C₄ alkylaminosulfonyl, di-C₁-C₄ alkylaminosulfonyl, nitro, cyano, formyl, C₁-C₄ alkylcarbonylamino, C₁-C₄ alkylcarbonyl, benzoyl, benzylcarbonyl or phenylethylcarbonyl; said substituted C₁-C₄ alkyl being substituted by hydroxy, C₁-C₄-alkoxy, acyloxy, amino, mono-C₁-C₄ alkylamino, di-C₁-C₄ alkylamino, acylamino, mercapto, C₁-C₄ alkylthio, halogen, C₁-C₄ alkylcarbonyl, carboxyl nitro, cyano, formyl, sulfo, a heterocyclic radical derived from a hexose or pentose, attached to the alkyl moiety directly via a ring atom or via an —O—, —S— or —NH-bridge or naphthyl, said acyl being derived from an aliphatic carboxylic acid having from 1 to 7 C-atoms, a phenyl carboxylic acid, unsubstituted or substituted by carboxy, hydroxy, halogen, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, nitro or amino, or a 5- or 6-membered aromatic heterocyclic carboxylic acid containing from 1 to 3 hetero-atoms each of which is N, O or S, unsubstituted or substituted by C₁ to C₄ alkyl, chlorine, bromine or amino; said naphthyl and phenyl (b) being unsubstituted or substituted by hydroxyl, amino, C₁-C₄ alkylamino, di-C₁-C₄ alkylamino, C₁-C₄ alkoxy, nitro, cyano, carboxy, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkyl, halogen, C₁-C₄ alkylthio, mercapto, C₁-C₄ alkylsulfonyl, sulfo, aminosulfonyl or C₁-C₄ alkylaminosulfonyl; R₂ is

wherein phenyl is unsubstituted or substituted by methyl, ethyl, methoxy, chlorine, bromine or nitro; R₃ is —H, —CH₃, —CH₂OH, —CH₂—NH₂, NHR′—CH₂—, NR′R″—CH₂—, R′CONH—CH₂, R′CO—NR″CH₂—, R′O—CH₂, R′COOCH₂—, R′SO₂NHCH₂—, R′SO₂—NR″CH₂—, R′NH—CO—NH—CH₂—, R′NHCS—NH—CH₂, R′O—CO—NH—CH₂—, wherein R′ and R″ are the same or different and each has the meaning hydrogen or C₁-C₃₀ alkyl, C₂-C₁₈ alkenyl, C₂-C₁₈ alkinyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C₃-C₈-cycloalkinyl or phenyl (a), said alkyl, cycloalkyl, cycloalkenyl and cycloalkinyl being unsubstituted or substituted by hydroxy, C₁-C₄-alkoxy, acyloxy, amino, mono-C₁-C₄ alkylamino, di-C₁-C₄ alkylamino, acylamino, mercapto, C₁-C₄ alkylthio, halogen, C₁-C₄ alkylcarbonyl, carboxyl, nitro, cyano, formyl, sulfo, a heterocyclic radical derived from a hexose or pentose, attached to the alkyl moiety directly via a ring atom or via an —O—, —S— or —NH-bridge, naphthyl or phenyl (b) said acyl being derived from an aliphatic carboxylic acid having from 1 to 7 C-atoms, a phenyl carboxylic acid, unsubstituted or substituted by carboxy, hydroxy, halogen, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, nitro or amino, or a 5- or 6-membered aromatic heterocyclic carboxylic acid containing from 1 to 3 hetero-atoms each of which is N, O or S, unsubstituted or substituted by C₁ to C₄ alkyl, chlorine, bromine or amino; said phenyl (a) being unsubstituted or substituted by C₁ to C₁₀ alkyl, C₁ to C₁₀ chloroalkyl, C₁ to C₁₀ nitroalkyl, C₁ to C₁₀ cyanoalkyl, C₁ to C₁₀ alkenyl, hydroxyl, C₁ to C₄ alkoxy, amino, mono-C₁ to C₄ alkylamino, di-C₁-C₄ alkylamino, mercapto, C₁-C₄ alkylthio, carboxyl, C₁-C₄-carbaloxy, sulfo, C₁-C₄ alkylsulfonyl, phenylsulfonyl, aminosulfonyl, C₁-C₄ alkylaminosulfonyl, di-C₁-C₄ alkylaminosulfonyl, nitro, cyano, formyl, C₁-C₄ alkylcarbonylamino, C₁-C₄ alkylcarbonyl, benzoyl, benzylcarbonyl or phenylethylcarbonyl; said napthyl and phenyl (b) being unsubstituted or substituted by hydroxyl, amino, C₁-C₄ alkylamino, di-C₁-C₄ alkylamino, C₁-C₄ alkoxy, nitro, cyano, carboxy, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkyl, halogen, C₁-C₄ alkylthio, mercapto, C₁-C₄ alkylsulfonyl, sulfo, aminosulfonyl or C₁-C₄ alkylaminosulfonyl;

U.S. Pat. No. 6,177,447, the entire teachings of which are incorporated herein by reference, discloses deoxynojirimycin compounds containing a hydrophobic moiety linked through a spacer to the nitrogen atom of deoxynojirimycin, and salts thereof, wherein the spacer comprises an alkoxy polyalkylene or polyalkylene chain of from 3 to 8 carbon atoms and the hydrophobic moiety is a polycyclic alcohol group containing three or more rings that each share two or more carbon atoms with another ring and is capable of inserting in lipid bilayers;

U.S. Patent Application Publication No. 2006/0058349, the entire teachings of which are incorporated herein by reference, discloses the following deoxynojirimycin analog:

wherein R is C₁₋₃alkylAr¹ where Ar¹ is phenyl or pyridyl; wherein phenyl is substituted by one or more substituents selected from CN, CON(R′)₂, SOnR², SO₂N(R¹)₂, N(R⁵)₂, N(R¹)COR², N(R¹)SOnR², C₀₋₆alkylAr², C₂₋₆ alkenylAr² and C₃₋₆ alkynylAr² wherein one or more of the —CH₂— groups of the alkyl chain may be replaced with a heteroatom selected from O, S and NR³, provided that when the heteroatom is 0, at least two —CH₂— groups separate it from any additional O atom in the alkyl chain; or two adjacent substituents on the Ar¹ phenyl may together form a fused 5- or 6-membered saturated or unsaturated ring wherein the ring optionally contains 1 or 2 heteroatoms selected from O, S and NR⁴ and is optionally substituted by one or more substituents selected from, an oxo group, C₁₋₆alkyl and C₀₋₃alkylAr⁴; and the Ar¹ phenyl is optionally substituted by one or more additional substituents selected from F, Cl, Br, CF₃, OCF₃, OR₃ and C₁₋₆alkyl; and wherein pyridyl is substituted by one or more substituents, selected from, CN, CON(R¹)₂, SOnR², SO₂N(R¹)₂, N(R⁵)₂, N(R¹)COR², N(R¹)SOnR², F, Cl, Br, CF₃, OCF₃, OR³, C₁₋₆ alkyl, C₀₋₆alkylAr², C₂₋₆alkenylAr² and C₃₋₆ alkynylAr² wherein one of the —CH₂— groups of the alkyl chain may be replaced with a heteroatom selected from O, S and NR³, provided that when the heteroatom is O, at least two —CH₂— groups separate it from any additional O atom in the alkyl chain; or two adjacent substituents on the Ar¹ pyridyl may together form a fused 5- or 6-membered saturated or unsaturated ring wherein the ring optionally contains 1 or 2 heteroatoms selected from O, S and NR⁴ and is optionally substituted by one or more substituents selected from, an oxo group, C₁₋₆alkyl and C₀₋₃alkylAr⁴; R¹ is H, C₁₋₆alkyl optionally substituted by OH, Ar³, or C₁₋₆ alkylAr³, or the group N(R¹)₂ may form a 5- to 10-membered heterocyclic group optionally containing one or more additional heteroatoms selected from O, S and NR³ and is optionally substituted by an oxo group; R² is C₁₋₆alkyl optionally substituted by OH, Ar³, or C₁₋₆alkylAr³; R³ is H, or C₁₋₆alkyl; R⁴ is H, C₁₋₆alkyl or C₀₋₃alkylAr⁴; R⁵ is H, C₁₋₆alkyl optionally substituted by OH, Ar³, or C₁₋₆alkylAr³, or the group N(R⁵)₂ may form a 5- to 10-membered heterocylic group optionally containing one or more additional heteroatoms selected from O, S and NR³ and is optionally substituted by an oxo group; Ar² and Ar³ are independently phenyl or a 5- to 10-membered heteroaryl group containing, up to 3 heteroatoms selected from O, S and NR³, which may be optionally substituted by one or more substituents selected from F, Cl, Br, CN, CF₃, OCF₃, OR³ and C₁₋₆alkyl; Ar⁴ is phenyl or pyridyl either of which may be optionally substituted by one or more substituents selected from F, Cl, Br, CN, CF₃, OCF₃, OR³ and C₁₋₆alkyl; and n=0, 1 or 2;

U.S. Patent Application Publication No. 2006/0074107, the entire teachings of which are incorporated herein by reference, discloses the following deoxynojirimycin analog:

wherein R is C₁₋₁₆ straight or branched-chain alkyl, optionally substituted by C₃₋₇ cycloalkyl, and optionally interrupted by —O—, the oxygen being separated from the ring nitrogen by at least two carbon atoms, or C₁₋₁₀ alkylaryl where aryl is phenyl, pyridyl, thienyl or furyl wherein phenyl is optionally substituted by one or more substituents selected from F, Cl, Br, CF₃, OCF₃, OR¹, and C₁₋₁₆ straight or branched-chain alkyl; and R¹ is hydrogen, or C₁₋₆ straight or branched-chain alkyl;

U.S. Patent Application Publication No. 2007/0066581, the entire teachings of which are incorporated herein by reference, discloses the following deoxynojirimycin analog:

wherein R₁-R₅ each independently comprise H or (CH₂)nCH₃ or X; R₆ comprises H, CH₂OH or CH₂OX; m is 0 or 1; n is 0-9; a, b, c, d, e are chiral centra having an R or S configuration; and X comprises a large hydrophobic moiety and a spacer, whereby the hydrophobic moiety is linked through the spacer to the nitrogen atom or carbon atom concerned, and wherein the large hydrophobic moiety is derived from a polycyclic alcohol containing three or more rings each sharing two or more carbon atoms with another ring and is capable of inserting in lipid bilayers; and

U.S. Patent Application Publication No. 2007/0112028, the entire teachings of which are incorporated herein by reference, discloses the following iminosugar:

wherein R is phenylmethyl-, wherein phenyl is substituted by OR¹; and R¹ is C₄₋₅ alkyl.

Specific examples of the compounds of the invention are shown below:

and pharmaceutically acceptable salts thereof.

Other specific examples of the compounds of the invention include compounds shown in Tables 1-3 and those exemplified in the examples below, stereoisomers thereof, and pharmaceutically acceptable salts thereof.

Also included are solvates, hydrates or polymorphs of the disclosed compounds herein. Thus, it is to be understood that when any compound is referred to herein by name and structure, solvates, hydrates and polymorphs thereof are included.

The compounds of the invention may contain one or more chiral centers and/or double bonds and, therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. When compounds of the invention are depicted or named without indicating the stereochemistry, it is to be understood that both stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and stereoisomeric mixtures are encompassed. For example, the compound represented by Structural Formula (I) below has chiral centers 1 and 2. Accordingly, the compounds of the invention depicted by Structural Formula (I) include (1R,2R), (1R,2S), (1S,2R) and (1S,2S) stereoisomers and mixtures thereof.

As used herein, a racemic mixture means about 50% of one enantiomer and about 50% of is corresponding enantiomer relative to all chiral centers in the molecule. The invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of the compounds of the invention.

In some preferred embodiments, the compounds of the invention are (1R,2R) stereoisomers.

Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.

Included in the invention are pharmaceutically acceptable salts of the compounds disclosed herein. The disclosed compounds have basic amine groups and therefore can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, and tartaric acids). Compounds of the invention with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [e.g. (+)-tartrates, (−)-tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid.

When the stereochemistry of the disclosed compounds is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.

As used herein, the term “hydrolyzable group” means an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as improved water solubility, improved circulating half-life in the blood (e.g., because of reduced metabolism of the prodrug), improved uptake, improved duration of action, or improved onset of action; or 2) is itself biologically inactive but is converted to a biologically active compound. Examples of hydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

An “aliphatic group” is non-aromatic, consists solely of carbon and hydrogen and may optionally contain one or more units of unsaturation, e.g., double and/or triple bonds. An aliphatic group may be straight chained, branched or cyclic. When straight chained or branched, an aliphatic group typically contains between about one and about twenty carbon atoms, typically between about one and about ten carbon atoms, more typically between about one and about six carbon atoms. When cyclic, an aliphatic group typically contains between about three and about ten carbon atoms, more typically between about three and about seven carbon atoms. A “substituted aliphatic group” is substituted at any one or more “substitutable carbon atom”. A “substitutable carbon atom” in an aliphatic group is a carbon in an aliphatic group that is bonded to one or more hydrogen atoms. One or more hydrogen atoms can be optionally replaced with a suitable substituent group. A “haloaliphatic group” is an aliphatic group, as defined above, substituted with one or more halogen atoms. Suitable substituents on a substitutable carbon atom of an aliphatic group are the same as those for an alkyl group.

The term “alkyl” used alone or as part of a larger moiety, such as “alkoxy”, “haloalkyl”, “arylalkyl”, “alkylamine”, “cycloalkyl”, “dialkyamine”, “alkylamino”, “dialkyamino” “alkylcarbonyl”, “alkoxycarbonyl” and the like, includes as used herein means saturated straight-chain, cyclic or branched aliphatic group. As used herein, a C1-C6 alkyl group is referred to “lower alkyl.” Similarly, the terms “lower alkoxy”, “lower haloalkyl”, “lower arylalkyl”, “lower allylamine”, “lower cycloalkylalkyl”, “lower dialkyamine”, “lower alkylamino”, “lower dialkyamino” “lower alkylcarbonyl”, “lower alkoxycarbonyl” include straight and branched saturated chains containing one to six carbon atoms.

The term “alkoxy” means —O-alkyl; “hydroxyalkyl” means alkyl substituted with hydroxy; “aralkyl” means alkyl substituted with an aryl group; “alkoxyalkyl” mean alkyl substituted with an alkoxy group; “alkylamine” means amine substituted with an alkyl group; “cycloalkylalkyl” means alkyl substituted with cycloalkyl; “dialkylamine” means amine substituted with two alkyl groups; “alkylcarbonyl” means —C(O)—R*, wherein R* is alkyl; “alkoxycarbonyl” means —C(O)—OR*, wherein R* is alkyl; and where alkyl is as defined above.

The terms “amine” and “amino” are used interchangeably throughout herein and mean —NH₂, —NHR or —NR₂, wherein R is alkyl.

“Cycloalkyl” means a saturated carbocyclic ring, with from three to eight carbons.

The terms “haloalkyl” and “haloalkoxy” mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term “halogen” means F, Cl, Br or I. Preferably the halogen in a haloalkyl or haloalkoxy is F.

The term “acyl group” means —C(O)R, wherein R is an optionally substituted alkyl group or aryl group (e.g., optionally substituted phenyl). R is preferably an unsubstituted alkyl group or phenyl.

An “alkylene group” is represented by —[CH₂]_(Z)—, wherein z is a positive integer, preferably from one to eight, more preferably from one to four.

As used herein, the term “alkenyl” refers to a straight or branched hydrocarbon group that contains one or more double bonds between carbon atoms. Suitable alkenyl groups include, e.g., n-butenyl, cyclooctenyl and the like. An alkenyl group may be substituted.

The term “aryl group” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, includes carbocyclic aromatic rings and heteroaryl rings. The term “aromatic group” may be used interchangeably with the terms “aryl”, “aryl ring” “aromatic ring”, “aryl group” and “aromatic group”. An aromatic group typically has six-fourteen ring atoms. A “substituted aryl group” is substituted at any one or more substitutable ring atom.

Carbocyclic aromatic rings have only carbon ring atoms (typically six to fourteen) and include monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring systems in which two or more carbocyclic aromatic rings are fused to one another. Examples include 1-naphthyl, 2-naphthyl, 1-anthracyl.

The term “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroaryl group” and “heteroaromatic group”, used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to aromatic ring groups having five to fourteen ring atoms selected from carbon and at least one (typically 1-4, more typically 1 or 2) heteroatom (e.g., oxygen, nitrogen or sulfur). They include monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other carbocyclic aromatic or heteroaromatic rings. Examples of monocyclic heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl(e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl) and thienyl (e.g., 2-thienyl, 3-thienyl. Examples of monocyclic six-membered nitrogen-containing heteraryl groups include pyrimidinyl, pyridinyl and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl.

The term “non-aromatic heterocyclic group”, used alone or as part of a larger moiety as in “non-aromatic heterocyclylalkyl group”, refers to non-aromatic ring systems typically having five to twelve members, preferably five to seven, in which one or more ring carbons, preferably one or two, are each replaced by a heteroatom such as N, O, or S. A non-aromatic heterocyclic group can be monocyclic or fused bicyclic. A “nitrogen-containing non-aromatic heterocyclic group” is a non-aromatic heterocyclic group with at least one nitrogen ring atom.

Examples of non-aromatic heterocyclic groups include (tetrahydrofuranyl (e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), [1,3]-dioxalanyl, [1,3]-dithiolanyl, [1,3]-dioxanyl, tetrahydrothienyl (e.g., 2-tetrahydrothienyl, 3-tetrahydrothieneyl), azetidinyl (e.g., N-azetidinyl, 1-azetidinyl, 2-azetidinyl), oxazolidinyl (e.g., N-oxazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl), morpholinyl (e.g., N-morpholinyl, 2-morpholinyl, 3-morpholinyl), thiomorpholinyl (e.g., N-thiomorpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl), pyrrolidinyl (e.g., N-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl) piperazinyl (e.g., N-piperazinyl, 2-piperazinyl), piperidinyl (e.g., N-piperidinyl), 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), thiazolidinyl (e.g., 4-thiazolidinyl), diazolonyl and N-substituted diazolonyl. The designation “N” on N-morpholinyl, N-thiomorpholinyl, N-pyrrolidinyl, N-piperazinyl, N-piperidinyl and the like indicates that the non-aromatic heterocyclic group is attached to the remainder of the molecule at the ring nitrogen atom.

A “substitutable ring atom” in an aromatic group is a ring carbon or nitrogen atom bonded to a hydrogen atom. The hydrogen can be optionally replaced with a suitable substituent group. Thus, the term “substitutable ring atom” does not include ring nitrogen or carbon atoms which are shared when two aromatic rings are fused. In addition, “substitutable ring atom” does not include ring carbon or nitrogen atoms when the structure depicts that they are already attached to a moiety other than hydrogen.

An aryl group may contain one or more substitutable ring atoms, each bonded to a suitable substituent. Examples of suitable substituents on a substitutable ring carbon atom of an aryl group include halogen, alkyl, haloalkyl, Ar^(A), —OR^(A), —O(haloalkyl), —SR^(A), —NO₂, —CN, —N(R^(B))₂, —NR^(B)C(O)R^(A), —NR^(B)CO₂R^(C), —N(R^(B))C(O)N(R^(B))₂, —C(O)R^(A), —CO₂R^(A), —S(O)₂R^(A), —SO₂N(R^(B))₂, —S(O)R^(C), —NR^(B)SO₂N(R^(B))₂, —NR^(B)SO₂R^(C), —V_(A)—Ar^(A), —V_(A)—OR^(A), —V—O(haloalkyl), —V_(A)—SR^(A), —V_(A)—NO₂, —V_(A)—CN, —V_(A)—N(R^(B))₂, —V_(A)—NR^(B)C(O)R^(A), —V_(A)—NR^(B)CO₂R^(C), —V_(A)—N(R^(B))C(O)N(R^(B))₂, —V_(A)—C(O)R^(A), —V_(A)—CO₂R^(A), —V_(A)—S(O)₂R^(A), —V_(A)—SO₂N(R^(B))₂, —V_(A)—S(O)R^(C), —V_(A)—NR^(B)SO₂N(R^(B))₂, —V_(A)—NR^(B)SO₂R^(C), —O—V_(A)—Ar^(A), —O—V_(B)—N(R^(B))₂, —S—V_(A)—Ar^(A), —S—V_(B)—N(R^(B))₂, —N(R^(B))—V_(B)—Ar^(A), —N(R^(B))—V_(B)—N(R^(B))₂, —NR^(B)C(O)—V_(A)—N(R^(B))₂, —NR^(B)C(O)—V_(A)—Ar^(A), —C(O)—V_(A)—N(RB)₂, —C(O)—V_(A)—Ar^(A), —CO₂—V_(B)—NR^(B))₂, —CO₂—V_(A)—Ar^(A), —C(O)N(R^(B))—V_(B)—N(R^(B))₂, —C(O)N(R^(B))—V_(A)—Ar^(A), —S(O)₂—V_(A)—N(R^(B))₂, —S(O)₂—V_(A)—Ar^(A), —SO₂N(R^(B))—V_(B)—N(R^(B))₂, —SO₂N(R^(b))—V_(A)—Ar^(A), —S(O)—V_(A)—N(R^(B))₂, —S(O)—V_(A)—Ar^(A), —NR^(B)SO₂—V_(A)—N(R^(B))₂ or —NR^(B)SO₂—V_(A)—Ar^(A); or two adjacent substituents, taken together, form a methylenedioxy, ethylenedioxy or —[CH₂]₄— group.

Each V_(A) is independently a C1-C10 alkylene group.

Each V_(B) is independently a C2-C10 alkylene group.

Ar^(A) is a monocyclic aromatic group each substituted with zero, one or two groups independently selected from halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy or haloalkyl.

Each R^(A) is independently i) hydrogen; ii) an aromatic group substituted with zero, one or two groups represented by halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy or haloalkyl; or iii) an alkyl group optionally substituted with halogen, hydroxyl, alkoxy, nitro, cyano, alkoxycarbonyl, alkylcarbonyl or haloalkoxy.

Each R^(B) is independently R^(A), —CO₂R^(A), —SO₂R^(A) or —C(O)R^(A); or —N(R^(B))₂ taken together is an optionally substituted non-aromatic heterocyclic group.

Each R^(C) is independently: i) an aromatic group substituted with zero, one or two groups represented by halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy or haloalkyl; or ii) an alkyl group optionally substituted with halogen, hydroxyl, alkoxy, nitro, cyano, alkoxycarbonyl, alkylcarbonyl or haloalkoxy.

An alkyl or a non-aromatic heterocyclic group (including, but not limited to, non-aromatic heterocyclic groups represented by —N(R³¹)₂, —N(R⁴¹)₂, —N(R⁵¹)₂ and —N(R^(B))₂) may contain one or more substituents. Examples of suitable substituents for an alkyl or a ring carbon of a non-aromatic heterocyclic group include those listed above for a substitutable carbon of an aryl and the following: ═O, ═S, ═NNHR^(C), ═NN(R^(C))₂, ═NNHC(O)R^(C), ═NNHCO₂ (alkyl), ═NNHSO₂ (alkyl), ═NR^(C), Spiro cycloalkyl group, fused cycloalkyl group or a monocyclic non-aromatic nitrogen-containing heterocyclic group attached by a ring nitrogen atom (e.g., N-piperidinyl, N-pyrrolidinyl, N-azepanyl, N-morpholinyl, N-thiomorphinyl, N-piperazinyl or N-diazepanyl group). Each R^(C) is independently selected from hydrogen, an unsubstituted alkyl group or a substituted alkyl group. Examples of substituents on the alkyl group represented by R^(C) include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl. Preferred substituents for an alkyl or a ring carbon of a non-aromatic heterocyclic group include C1-C2 alkyl, —OH, N-pyrrolidinyl, N-piperidinyl, N-(4-alkyl)piperazinyl, N-morpholinyl or N-pyrrolyl.

Suitable substituents on the nitrogen of a non-aromatic heterocyclic group or heteroaryl group include —R^(D), —N(R^(D))₂, —C(O)R^(D), —CO₂R^(D), —C(O)C(O)R^(D), —C(O)CH₂C(O)R^(D), —SO₂R^(D), —SO₂N(R^(D))₂, —C(═S)N(R^(D))₂, —C(═NH)—N(R^(D))₂, and —NR^(D)SO₂R^(D); wherein R^(D) is hydrogen, an alkyl group, a substituted alkyl group, phenyl (Ph), substituted Ph, —O(Ph), substituted —OPh), CH₂(Ph), substituted CH₂(Ph), or an unsubstituted heteroaryl or heterocyclic ring. Examples of substituents on the alkyl group or the phenyl ring represented by R^(D) include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl. Preferred substituents on a substitutable nitrogen atom of a nitrogen-containing heteroaryl or nitrogen-containing non-aromatic heterocyclic group include C1-C2 alkyl, C1-C2 hydroxyalkyl, or benzyl optionally substituted with halogen, nitro, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy.

In some specific embodiments, non-aromatic heterocyclic groups (including, but not limited to, non-aromatic heterocyclic groups represented by —N(R³¹)₂, —N(R⁴¹)₂, —N(R⁵¹)₂ and —N(R^(B))₂) each independently are optionally substituted with one or more substituents selected from the group consisting of halogen, ═O, ═S, ═N(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, (C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino and (C1-C6 dialkyl)amino. In some more specific embodiments, the non-aromatic heterocyclic groups each independently are optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, (C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino and (C1-C6 dialkyl)amino.

As used herein, a bridged heterobicyclic ring means two rings having at least three adjacent ring carbon atoms in common.

As used herein a subject is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, such as a companion animal (e.g., dogs, cats, and the like), a farm animal (e.g., cows, sheep, pigs, horses, and the like) or a laboratory animal (e.g., rats, mice, guinea pigs, and the like). Subject and patient are used interchangeably. A subject “in need of treatment” includes a subject with chronic renal failure.

“Treatment” or “treating” refers to both therapeutic and prophylactic treatment.

An “effective amount” of a pharmaceutical composition disclosed above is a quantity that results in a beneficial clinical outcome of or exerts an influence on, the condition being treated with the pharmaceutical composition compared with the absence of treatment. The administering amount of a pharmaceutical composition disclosed above to the subject will depend on the degree, severity, and type of the disease or condition, the amount of therapy desired, and the release characteristics of the pharmaceutical composition. It will also depend on the subject's health, size, weight, age, sex, and tolerance to drugs. Typically, the pharmaceutical compositions of the invention are administered for a sufficient period of time to achieve the desired therapeutic effect. Dosages may range from 0.1 to 500 mg/kg body weight per day. In one embodiment, the dosing range is 1-20 mg/kg/day. The compound of the invention may be administered continuously or at specific timed intervals. For example, the compound of the invention may be administered 1, 2, 3, or 4 times per day, such as, e.g., a daily or twice-daily formulation. Commercially available assays may be employed to determine optimal dose ranges and/or schedules for administration. For example, assays for measuring blood glucose levels are commercially available (e.g., OneTouch® Ultra®, Lifescan, Inc. Milpitas, Calif.). Kits to measure human insulin levels are also commercially available (Linco Research, Inc. St. Charles, Mo.). Additionally, effective doses may be extrapolated from dose-response curves obtained from animal models (see, e.g., Comuzzie et al., Obes. Res. 11 (1):75 (2003); Rubino et al., Ann. Surg. 240(2):389 (2004); Gill-Randall et al., Diabet. Med. 21 (7):759 (2004), the entire teachings of which are incorporated herein by reference). Therapeutically effective dosages achieved in one animal model can be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219 (1996), the entire teachings of which are incorporarted herein by reference) and Table A below for equivalent surface area dosage factors.

From: Mouse Rat Monkey Dog Human (20 g) (150 g) (3.5 kg) (8 kg) (60 kg) To: Mouse 1 ½ ¼ ⅙   1/12 To: Rat 2 1 ½ ¼ 1/7 To: Monkey 4 2 1 ⅗ ⅓ To: Dog 6 4 ⅗ 1 ½ To: Human 12 7 3 2 1

Typically, the pharmaceutical compositions of the invention can be administered before or after a meal, or with a meal. As used herein, “before” or “after” a meal is typically within two hours, preferably within one hour, more preferably within thirty minutes, most preferably within ten minutes of commencing or finishing a meal, respectively.

In one embodiment, the method of the present invention is a mono-therapy where the pharmaceutical compositions of the invention are administered alone. Accordingly, in this embodiment, the compound of the invention is the only pharmaceutically active ingredient in the pharmaceutical compositions.

In another embodiment, the method of the invention is a co-therapy with other therapeutically active drugs known in the art for treating the desired diseases or indications, such as one or more known drugs for treating, diabetes, lysosomal diseases, tumors, etc.

In a particular embodiment, the method of the invention is a combination therapy for treating a glomerular disease selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis and membranous nephropathy. The combination therapy comprise any of the compounds of the invention described herein and at least one other compound suitable for treating glomerular disease.

The pharmaceutical compositions of the invention optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5^(th) Ed., Pharmaceutical Press (2005)).

The carriers, diluents and/or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof. The pharmaceutical compositions can conveniently be presented in unit dosage form and can be prepared by any suitable method known to the skilled artisan. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing into association the compounds disclosed herein with the carriers, diluents and/or excipients and then, if necessary, dividing the product into unit dosages thereof.

The pharmaceutical compositions of the invention can be formulated as a tablet, sachet, slurry, food formulation, troche, capsule, elixir, suspension, syrup, wafer, chewing gum or lozenge. A syrup formulation will generally consist of a suspension or solution of the compounds of the invention described herein or salt in a liquid carrier, for example, ethanol, glycerine or water, with a flavoring or coloring agent. Where the composition is in the form of a tablet, one or more pharmaceutical carriers routinely used for preparing solid formulations can be employed. Examples of such carriers include magnesium stearate, starch, lactose and sucrose. Where the composition is in the form of a capsule, the use of routine encapsulation is generally suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule, pharmaceutical carriers routinely used for preparing dispersions or suspensions can be considered, for example, aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.

Though the above description is directed toward routes of oral administration of pharmaceutical compositions consistent with embodiments of the invention, it is understood by those skilled in the art that other modes of administration using vehicles or carriers conventionally employed and which are inert with respect to the compounds of the invention may be utilized for preparing and administering the pharmaceutical compositions. For example, the pharmaceutical compositions of the invention may also be formulated for rectal administration as a suppository or retention enema, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. Also, the pharmaceutical compositions of the invention can be formulated for injection, or for transdermal or transmucosal administration. Illustrative of various modes of administration methods, vehicles and carriers are those described, for example, in Remington's Pharmaceutical Sciences, 18^(th) ed. (1990), the disclosure of which is incorporated herein by reference.

The invention is illustrated by the following examples which are not intended to be limiting in any way.

EXEMPLIFICATION Example 1 General Methods for the Preparation of Compounds of the Invention

A general method for the synthesis of final compounds is depicted in Scheme 1. A general method for the preparation of the compounds of the invention involves the reaction of the amine of type EVII with the appropriate reagent. The amine type EVII, such as (1R,2R)-2-amino-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl) propan-1-ol, can be prepared according to the preparation of intermediate 4 of U.S. Pat. No. 6,855,830 (the entire teachings of which are incorporated herein by reference), or by using the general synthetic procedures depicted in schemes 2-5. Final amide compounds, EIX can be prepared by reaction of the amine EVII with the corresponding acylating agent using standard reaction conditions for the formation of an amide. The urea compounds, EIIX can be prepared by reaction of the amine EVII with the corresponding isocyanate. The carbamates, EX can be prepared by reaction of the amine EVII with the corresponding chloroformate.

Example 1A Synthesis of the Compounds of the Invention: General Methods for the Preparation of Amide Analogs

Method 1

A mixture of Compound EVII (1 mmol), such as (1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol, prepared according to the preparation of intermediate 4 of U.S. Pat. No. 6,855,830 (the entire teachings of which are incorporated herein by reference) or using the methods depicted in schemes 2, 3, 4 and 5, an acid (1.2 mmol), DCC (dicyclohexylcarbodiimide, 1.2 mmol) and HOBT (1-hydroxy benzotriazole, 1.2 mmol) was dissolved in CH₂Cl₂ (5 ml). The mixture was stirred at room temperature and monitored by TLC (thin liquid chromatography) for completion. After completion the mixture was filtered and purified by column chromatography using, for example, a mixture of (CH₂Cl₂/MeOH/NH₄OH).

Method 2

A mixture of Compound EVII (1 mmol), such as (1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol, prepared according to the preparation of intermediate 4 of U.S. Pat. No. 6,855,830 (the entire teachings of which are incorporated herein by reference) or using the methods depicted in schemes 2, 3, 4 and 5, an acid and DCC (dicyclohexylcarbodiimide, 1.2 mmol) was dissolved in CHCl₃ (5 ml). The mixture was placed in the microwave reactor (T=120° C., time=1 min) and it was then filtered and purified by column chromatography using, for example, a mixture of (CH₂Cl₂/MeOH/NH₄OH).

Method 3

A mixture of Compound EVII (1 mmol), such as (1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol, prepared according to the preparation of intermediate 4 of U.S. Pat. No. 6,855,830 (the entire teachings of which are incorporated herein by reference) or using the methods depicted in schemes 2, 3, 4 and 5, an acid chloride (1.2 mmol) and K₂CO₃ (2 mmol) was suspended in THF (5 ml). The mixture was stirred at room temperature and monitored by TLC for completion. After completion, the mixture was filtered and purified by column chromatography using, for example, a mixture of (CH₂Cl₂/MeOH/NH₄OH).

Method 4

Compound EVII, such as (1R,2R)-2-amino-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-pyrrolidin-1-yl-propan-1-ol, prepared according to the preparation of intermediate 4 of U.S. Pat. No. 6,855,830 (the entire teachings of which are incorporated herein by reference) or using the methods depicted in schemes 2, 3, 4 and 5, was coupled with a variety of N-hydroxysuccinamide esters in methylene chloride under an atmosphere of nitrogen, for example, for 18 to 24 hours depending on the ester used.

Preparation of N-Hydroxysuccinamide Esters

Various mono- and di-keto acids were coupled with N-hydroxysuccinamide in the presence of N,N¹-dicyclohexylcarbodiimide in ethyl acetate under an atmosphere of nitrogen for 18 hours. The products were filtered to remove the dicyclohexylurea. The identity of these esters was confirmed by ¹H NMR and the crude material was then used in the preparation of amide analogs without further purification.

Example 1B Alternative Synthetic Method for the Preparation of Intermediate EVII. Synthetic Route 1

An alternative general synthesis of Compound EVII is depicted in Scheme 2. Treatment of (R)-2-(benzyloxycarbonylamino)-3-hydroxypropanoic acid with EDCI and N,O-dimethylhydroxyamine gave the weinreb amide EI in excellent yield. The primary alcohol was protected as the TBDMS ether EII in excellent yield by reaction with TBDMSCl in DMF. Reaction of EII with a grignard at low temperature gave EIII in good to excellent yields. Steroselective reduction of EIII and with L-selectride at −70° C. gave EIV in good to excellent yield and selectivity. Compound EV was obtained in good to excellent yields after deprotection with acetic acid. Reaction with mesylate chloride and a suitable amine produced EVI in good to excellent yield. Finally, deprotection to the primary amine EVII was done in the microwave oven using NaOH aqueous solution in methanol at 150° C. for one to three minutes depending on the specific compound.

Example 1B Alternative Synthetic Method for the Preparation of Intermediate EVII. Synthetic Route 2

An alternative general synthesis of Compound EVII is depicted in Scheme 3. Intermediate AI was obtained with excellent diastereoselectivity (96:4) by reduction of compound A with LiAlH₄ followed by reaction with an aldehyde in the presence of CuI and Me₂S. Mesylate intermediate AIII was obtained by reaction with Amberlyst 15 followed by reaction with MsCl in pyridine. The final compound EVII was obtained by reaction with pyrrolidine and removal of the CBz by hydrogenation.

Example 1B Alternative Synthetic Method for the Preparation of Intermediate EVII. Synthetic Route 3

A general alternative route for synthesis of compound EVII is depicted in Scheme 4. Intermediate EIV was obtain as shown in Scheme 4 was cycled into oxazolidinone B using sodium hydride in a DMF/THF solution. Deprotection of the primary alcohol by reaction with nBu₄NF, followed by formation of the tosylate by reaction with tosyl chloride in pyridine, finally, displacement of the tosylate by an appropriate amine afforded compound B1 in good to excellent yield. Hydrolysis of the oxazolidinone with LiOH in a water ethanol mixture gave compound EVII.

Example 1B Alternative Synthetic Method for the Preparation of Intermediate EVII. Synthetic Route 4

An alternative general synthesis of Compound EVII is depicted in Scheme 5. An aldehyde (2 equiv) is condensed with the chiral morpholinone in toluene with removal of water to provide the fused cycloadduct 2. Treatment of 2 with hydrogen chloride in an alcohol solvent such as methanol provides amino acid 3. Removal of the N-benzyl functionality can be accomplished with hydrogen in the presence of a palladium catalyst to afford 4. Cyclization of 4 with triphosgene and base provides ester 5. The ester functionality can be reduced with sodium borohydride, and the resulting alcohol converted to an appropriate leaving group (i.e. tosylate or iodide). Reaction of 6 with a suitable amine in the presence of excess base (e.g. K₂CO₃) in a polar solvent (e.g. DMSO or CH₃CN) affords 7. Final deprotection under basic conditions affords Compound EVII analogs suitable for conversion to the desired amide final products.

Example 1C Preparation of Compound EVII using Scheme 2

Preparation of EII: (R)-benzyl 3,8,8,9,9-pentamethyl-4-oxo-2,7-dioxa-3-aza-8-siladecan-5-ylcarbamate

Imidazole (1.8 g, 26.5 mmol) was added to a solution of (R)-benzyl 3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 10.6 mmol) in DMF (dimethyl formamide, 15 mL) followed by TBDMSiCl (tert-butyldimethylsilyl chloride, 2.4 g, 15.95 mmol). The reaction stirred for 12 hrs at room temperature under nitrogen atmosphere and was quenched with aqueous ammonium chloride (100 ml). The aqueous layer was extracted with methylene chloride (200 mL) and ethyl acetate (100 mL) and the organic layers were washed with brine and concentrated. The crude product was purified by column chromatography using 10% EtOAc (ethylacetate)-hexanes to give an oil (3 g, 74% yield). ¹H NMR (400 MHz, CDCl₃) δ=0 (s, 6H), 0.9 (s, 9H), 3.2 (s, 3H), 3.8 (s, 3H), 3.8-3.9 (m, 2H), 4.8 (broad s, 1H), 5.1 (q, 2H), 5.7 (d, 1H), 7.2-7.4 (m, 5H).

Preparation of EIII: (R)-benzyl 3-(tert-butyldimethylsilyloxy)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-oxopropan-2-ylcarbamate

(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)magnesium bromide (26 g, 78 mmol) dissolved in 40 mL of THF (tetrahydrofuran) under a nitrogen atmosphere was cooled down to −70° C. and (R)-benzyl 3,8,8,9,9-pentamethyl-4-oxo-2,7-dioxa-3-aza-8-siladecan-5-ylcarbamate (12.3 g, 3 μmol) dissolved in THF (13 ml) were added dropwise. The reaction mixture was allowed to warm up to −15° C. and left to react for 12 hrs followed by stirring at room temperature for 2 hrs. After cooling the reaction mixture to −40° C. it was quenched using aqueous ammonium chloride and the aqueous layer was extracted with EtOAc dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography using 25% EtOAc-hexanes to give pure product (13 g, 88% yield). ¹H NMR (400 MHz, CDCl₃) γ=0 (d, 6H), 0.9 (s, 9H), 4.0-4.2 (m, 2H), 4.4 (s, 2H), 4.5 (s, 2H), 5.2 (s, 2H), 5.4 (m, 1H), 6.1 (d, 1H), 7 (d, 1H), 7.4-7.7 (m, 7H).

Preparation of EIV: benzyl (1R,2R)-3-(tert-butyldimethylsilyloxy)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxypropan-2-ylcarbamate

(R)-benzyl 3-(tert-butyldimethylsilyloxy)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-oxopropan-2-ylcarbamate (3.1 g, 6.6 mmol) were dissolved in THF (25 ml) and cooled down to −70° C. under nitrogen atmosphere. L Selectride (13.2 ml of 1M solution in THF, 13 mmol) was added dropwise while keeping the temperature at −70° C. After 1 hour, the reaction was quenched with a 1M aqueous solution of potassium tartrate (13 ml) and extracted with EtOAc. The organic layer was evaporated down and the product was purified by column chromatography using 2.5% EtOAc-2% acetone-methylene chloride. The desired diastereomer was obtained in 80% yield (2.5 g). ¹H NMR (400 MHz, CDCl₃) δ=0 (d, 6H), 0.9 (s, 9H), 3.5 (broad s, 1H), 3.7-3.9 (m, 2H), 4.2 (s, 4H), 4.9 (broad s, 1H), 5.0 (d, 2H), 5.4 (d, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2-7.4 (m, 5H).

Preparation of EV: benzyl (1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1,3-dihydroxypropan-2-ylcarbamate

Benzyl (1R,2R)-3-(tert-butyldimethylsilyloxy)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxypropan-2-ylcarbamate (0.5 g) was dissolved in a 4 ml mixture of Acetic acid/THF/water (3/1/1) and left to stir over night. The crude was evaporated down and the product azeotropically dried with EtOAc (10 ml). The crude product was purified by column chromatography using 50% EtOAc-hexane. The pure product was obtained in 74% yield (0.28 g). ¹H NMR (400 MHz, CDCl₃) δ=3.4-3.8 (m, 4H), 4.1 (broad s, 4H), 4.8 (s, 1H), 4.9 (broad s, 2H), 5.7 (broad s, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2-7.4 (m, 5H).

General Procedure for Preparation of EVI and EVII

Benzyl (1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1,3-dihydroxypropan-2-ylcarbamate was dissolved in excess pyridine, cooled to −15° C. and one equivalent of methanosulfonyl chloride was added to the mixture. Mixture was stirred about half an hour, and ten equivalents of the amine were added. The reaction mixture was allowed to warm up to room temperature and then heated at 50° C. overnight. The crude was evaporated down and the product was purified by column chromatography using a mixture of methanol/methylene chloride/ammonium hydroxide. The pure compound EVI was then de-protected by hydrolysis in the microwave, using aqueous NaOH (40% in weight)/methanol solution as solvent and heating the mixture to 150° C. for about 15 minutes to give the free amines of the type EVI. The final product was purified by silica-gel column chromatography using a mixture of methanol/methylene chloride/ammonium hydroxide.

Examples of EVII Compounds i) (1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-morpholinopropan-1-ol

¹H NMR (400 MHz, CDCl₃) δ=2.3 (dd, 2H), 2.4 (dd, 2H), 2.5-2.6 (m, 2H), 3.2 (m, 1H), 3.6-3.7 (m, 4H), 4.2 (s, 4H), 4.4 (d, 1H), 6.5-6.9 (m, 3H); MS for C₁₅H₂₂N₂O₄ m/z 294.8 [M+11].

ii) (1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(piperidin-1-yl)propan-1-ol

¹H NMR (400 MHz, CDCl₃) δ=1.4 (broad s, 2H), 1.7 (m, 4H), 2.2-2.6 (m, 6H), 3.2 (m, 1H), 4.2 (s, 4H), 4.5 (s, 1H), 6.7-6.9 (m, 3H).

Example 1D Preparation of Substituted Phenoxy Propionic Acids Example 1D1 Preparation of 3-(4-methoxyphenoxy)propionic acid i) 3-(4-methoxyphenoxy)propionitrile

A 740 g (5.96 mol, 1 eq.) sample of 4-methoxyphenol was charged to a 3 necked 5 L flask under nitrogen. Triton B (50 mL of a 30% wt. solution in methanol) was charged to the flask, and stirring initiated via an overhead stirrer. Acrylonitrile (2365 mL, 35.76 mol, 6 eq.) was then charged to the reaction flask in a single portion, and the reaction mixture heated at 78° C. for 36 h. HPLC analysis indicated that the reaction was complete at this point. Solvents were removed via rotary evaporation, and the resulting oil was chased with toluene to remove excess acrylonitrile. The crude material was recrystallized from TBME (tert-butyl methyl ether) 10 volumes relative to the crude weight), and dried in a vacuum oven to give 945 g of 3-(4-methoxyphenoxy)propionitrile as white crystals (Yield: 89.48%). ¹H NMR (450 MHz, CDCl₃): δ=2.72 (t, 2H; CH₂CN); δ=3.83 (s, 3H; OCH₃); δ=4.05 (t, 2H; OCH₂); δ=6.70 (m, 4H; Ar—H); ¹³C NMR (112.5 MHz, CDCl₃): d=18.843 (CH₂CN); 55.902 (OCH₃); 63.699 (OCH₂); 114.947 (CH₃OCCH); 116.183 (CH₂OCCH); 117.716 (CN); 151.983 (CH₃OC); 154.775 (CH₂OC).

ii) 3-(4-methoxyphenoxy)propionic acid

A 945 g (5.34 mol, 1 eq.) sample of 1 (3-(4-methoxyphenoxy)propionitrile was charged to a 22 L round bottom flask equipped with an overhead stirrer under N2. To the stirred solids, 4 L of concentrated HCl was slowly added, followed by 2 L of H₂O. The reaction mixture was heated to 100° C. for 3.5 h, at which point the reaction was complete by HPLC analysis. The reaction was cooled to 10° C. by the addition of ice to the reaction mixture, and was filtered. The dried solids gave 920 g of crude 3-(4-methoxyphenoxy)propionic acid. The crude material was dissolved in 5 L of 6 wt. % sodium carbonate (such that pH=9), and 2 L of DCM (dichloromethane) was added to the reaction vessel. After stirring thoroughly, the organic layer was separated and discarded via a separatory funnel, and the aqueous layer charged back into the 22 L flask. The pH of the aqueous layer was carefully adjusted to 4.0, by slow addition of 6 M HCl. The precipitated solids were filtered, and dried in a vacuum oven to give 900 g of 3-(4-methoxyphenoxy)propionic acid as a white solid (Yield: 86.04%). ¹H NMR (450 MHz, CDCl₃); δ=2.78 (t, 2H; CH₂COOH); 3.70 (s, 3H; OCH₃); 4.18 (t, 2H; OCH₂); 6.78 (m, 4H; Ar—H); ¹³C NMR (112.5 MHz, CDCl₃): δ=34.703 (CH₂COOH); 55.925 (OCH₃); 64.088 (OCH₂); 114.855 (CH₃OCCH); 115.984 (CH₂OCCH); 152.723 (CH₃OC); 154.302 (CH₂OC); 177.386 (COOH).

Example 1D2 Preparation of 3-(4-(3-oxobutyl)phenoxy)propanoic acid

Step 1: a mixture of 4-(p-hydroxyphenol)-2-butanone (1.032 g), triton B (400 μL), acrylonitrile (4 mL) and MeOH (0.8 mL) was heated at 70° C. for 20 hours. The mixture was cooled to room temperature and the solvent was removed to dryness. 3-(4-(3-oxobutyl)phenoxy)propanenitrile was obtained as a white solid (0.572 g) after purification by column chromatography using ethyl acetate/hexane.

Step 2: 3-(4-(3-oxobutyl)phenoxy)propanenitrile (0.478 g) was suspended in HCl (37%, 5 mL) and placed in the microwave reactor (T=110° C., 5 min). The mixture was poured onto iced water (20 g), filtered, and the solid was washed with water (2×5 mL). After column chromatography purification using a mixture of methylene chloride/methanol, 3-(4-(3-oxobutyl)phenoxy)propanoic acid was obtained as a white solid (0.3 g). ¹H NMR (CDCl₃, 400 mHz, ppm); 2.2 (s, 3H), 2.7 (t, 2H), 2.85 (m, 4H), 4.25 (t, 2H), 6.8 (d, 2H), 7.1 (d, 2H).

Example 1D3 Preparation of 3-(4-(2-methoxyethyl)phenoxy)propanoic acid

Step 1: a mixture of 4-(2-methoxy ethyl) phenol (1.547 g, 10.3 mmol), propiolic acid tert-butyl ester (1.367 g, 10.8 mmol) and N-methyl morpholine (1.18 mL, 10.8 mmol) in CH₂Cl₂ (15 mL) was stirred at room temperature for 24 hours. The mixture was absorbed on SiO₂ (20 g) and purified by column chromatography using a mixture of methylene chloride/hexane. The product was obtained as a two to one mixture of (E)/(Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate isomers (2.0 g).

Step 2: (E)/(Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate (0.57 g) was suspended in a mixture of THF (5 mL)/HCl (2 M, 5 mL) and placed in the microwave reactor (T=100° C., 15 sec). THF was removed by rotary evaporation and the mixture was extracted with CH₂Cl₂ (10 mL). (E)/(Z)-3-(4-(2-methoxyethyl)phenoxy)acrylic acid was obtained as a white solid after purification by column chromatography using a mixture of hexane/ethyl acetate.

Step 3: (E)/(Z)-3-(4-(2-methoxyethyl)phenoxy)acrylic acid (0.3 g) was dissolved in EtOH (10 mL) and Pd/C (5%, degussa type E101, 40 mg) was added. The mixture was hydrogenated at atmospheric pressure for 2 hours and then filtered and the solvent removed to dryness. After purification by column chromatography using a mixture of hexane/ethyl acetate, 3-(4-(2-methoxyethyl)phenoxy)propanoic acid was obtained as a white solid (0.236 g). ¹H NMR (CDCl₃, 400 mHz, ppm); 2.85 (t, 4H), 3.35 (s, 3H), 3.55 (t, 2H), 4.25 (t, 2H), 6.85 (d, 2H), 7.1 (d, 2H).

Example 1D4 Preparation of 3-(4-(3-methylbutanoyl)phenoxy)propanoic acid

Step 1: 3-phenoxypropionic acid (5.0 g, 30 mmol) was dissolved in MeOH (12 mL) and H₂SO₄ (18 M, 3 drops) was added. The mixture was place in the microwave reactor (T: 140° C., t: 5 min). The solvent was evaporated, the mixture was partitioned in EtOAc (30 mL) and NaOH (2N, 20 mL). The organic phase was dried over MgSO₄, filtered, and evaporated to give methyl 3-phenoxypropanoate (5.0 g, 27.7 mmol, 92.5%).

Step 2: aluminum chloride (1.1 g, 8.34 mmol) was added to a cold solution (0° C.) solution of methyl 3-phenoxypropanoate (1.0 g, 5.56 mmol) and tert-butylacetyl chloride (1.25 mL, 8.34 mmol) in CH₂Cl₂ (9 mL) and the reaction mixture was stirred overnight. The mixture was evaporated and the residue was diluted with EtOAc (30 mL) and then washed with water (2×20 mL). The organic phase was removed and purified with silica chromatography using of a gradient hexanes/EtOAc (100:0→0:100) to give methyl 3-phenoxypropanoate (600 mg, 2.27 mmol, 40%).

Step 3: a solution of methyl 3-phenoxypropanoate (200 mg, 0.76 mmol) in 2 mL of HCl (37%) was placed in a microwave reactor (T: 120° C., t: 5 min). The mixture was poured into iced water (2 g) and washed with EtOH (3×10 mL). The organic phase was combined and evaporated. The crude product was purified with silica gel chromatography using of a gradient hexanes/EtOAc (100:0→0:100) to give 3-(4-(3-methylbutanoyl)phenoxy)propanoic acid (120 mg, 0.48 mmol, 63%).

Example 2 Preparation of Compounds of the Invention

The exemplary compounds shown in Example 2 and Tables 1-3 can be prepared by following scheme 1 described above, Detailed synthetic description of certain compounds also are described below as examples.

Example 2E1 Preparation of Hemi-Hydrate of Compound 163 N-[2-Hydroxy-2-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-pyrrolidin-1-ylmethyl-ethyl]-3-(4-methoxy-phenoxy)-propionamide

Compound 163 was prepared by following Scheme 1A above. 3-(4-methoxyphenoxy)propanoic acid (see Example 1D1, 34.47 g, 169 mmol, 96% purity by HPLC), DCC (34.78 g, 169 mmol) and N-hydroxysuccinimide (19.33, 169 mmol) were combined as dry powders and methylene chloride (500 mL) was added. The suspension was mechanically stirred overnight, ambient temperature, under a nitrogen atmosphere. HPLC analysis showed complete conversion of the acid to the NHS ester (N-hydroxy succinyl ester). To the mixture was added (1R,2R)-2-amino-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-pyrrolidin-1-yl-propan-1-ol (50 g, 169 mmol) and stirring continued for 2.5 hours. HPLC showed conversion to the product and loss of both the NHS ester and step 5 amine. The reaction mixture was vacuum filtered on a Büchner funnel to remove DCC urea. The solid urea was washed with 500 mL of methylene chloride. The organic layers were combined, placed in a separatory funnel, and treated with 500 mL of 1.0M NaOH. The layers were separated, and the cloudy organic layer was recharged into a separatory funnel and treated with a 6% HCl solution (adjusted to pH=0.03-0.34, 100 mL of solution). Two clear layers formed. The resultant biphasic solution was poured into an Erlenmeyer flask and cautiously neutralized to a pH of 7.2-7.4 with a saturated solution of sodium bicarbonate (approx 200 mL of solution). The organic layer was separated from the aqueous layer, dried over sodium sulfate and evaporated to yield 83.6 g of yellow oil (theoretical yield: 77.03 g). The oil was dissolved in isopropyl alcohol (500 mL) with heating and transferred to a 1 L round bottom flask equipped with a mechanical stirrer and heating mantel. The solution was heated to 50° C. and the mechanical stirrer was set to a rate of 53-64 rpm. Tartaric acid (25.33 g, 168 mmol) was dissolved in deionized water (50 mL) and added to the stirred solution at 50° C. Once the solution turned from milky white to clear, seed crystals were added to the mixture and crystallization immediately began (temperature jumped to 56° C.). After 20 minutes, the mixture was set to cool to a temperature of 35° C. (cooling took 1.15 hours). Heating was removed and the solution was allowed to stir for 12 hours. The resulting thick slurry was filtered on a Büchner funnel. Any remaining solid in the flask was washed onto the funnel using ice-cold isopropyl alcohol (100 mL). The material was transferred to a drying tray and heated to 48° C. under vacuum for 3 days (after two days the material weighed 76 g and after three days it weighed 69.3 g). The solid was analyzed by LC and shown to be 98.1% pure (AUC), the residual solvent analysis showed the material to possess 3472 ppm of isopropyl alcohol, and the DSC (differential scanning calroimetery) showed a melting point of 134.89° C. A total of 69.3 g of white solid was collected (65.7% overall yield). ¹H NMR (400 MHz, CDCl₃) δ=1.8 (M, 4H), 2.4-2.6 (m, 4H), 2.6 (m, 1H), 2.85 (m, 2H), 3.0 (m, 1H), 3.65 (s, 3H), 3.8 (m, 2H), 3.86 (2, 2H), 4.18 (br s, 5H), 4.6 (s, 1H), 6.6-6.8 (m, 7H), 7.8 (d, 1H); MS for C₂₉H₄₀N₂O₁₃ m/k 457.3 [M+H] for main peak (free-base).

Example 2E2 Preparation of Compound 247: N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-3-(p-tolyloxy)propanamide

Compound 247 was prepared by reaction of (1R,2R)-2-amino-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-1-ol as the amine, prepared according to scheme 3 with 3-(4-methylphenoxy)propionic acid using method 1.

Preparation of A: (R)-benzyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate

N,O-dimethylhydroxylamine hydrochloride (45 g, 0.46 mmol, 1.5 eq) and N-methyl morpholine (84 mL, 0.765 mol, 2.5 eq.) were added slowly to a cold (−15° C.) suspension of d-CBz serine (73.0 g, 0.305 mol) in CH₂Cl₂ (560 mL) keeping the temperature below −5° C. The mixture was cooled back to ˜−15° C. and EDCI (62 g, 0.323 mol, 1.05 eq) was added. The mixture was stirred for 5 hours keeping the temperature below 5° C. The solvent was removed by rotary evaporation and the mixture was partitioned between HCl (1 M, 300 mL) and EtOAc (500 mL). The organic layer was separated and washed with HCl (1 M, 2×100 mL) and then sat. NaHCO₃ (2×150 mL). The mixture was dried over MgSO₄, filtered and then the solvent was removed by rotary evaporation. (R)-benzyl 3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate was re-dissolved in a mixture of acetone (375 mL) and 2,2-dimethoxy propane (375 mL) and boron trifluoride ethereate (3 mL) was added. The mixture was stirred at room temperature for 5 hours and then triethyl amine (3 mL) was added. The solvent was removed to dryness and (R)-benzyl 4-(methoxy(methyl)carbamoyl)-2,2-dimethyloxazolidine-3-carboxylate was obtained as a white solid (73.0 g, 74% yield from both steps) after purification by column chromatography using a mixture of hexane/EtOAc/acetone.

¹H NMR (CDCl₃, 400 mHz, ppm); 1.5 (s, 2H), 1.6 (s, 3H), 1.7 (s, 2H), 1.75 (s, 3H), 3.14 (s, 3H), 3.24 (2H), 3.4 (3H), 3.76 (s, 2H), 4.0 (m, 1.7; H), 4.16 (m, 1H), 4.2 (m, 1.7), 4.78 (m, 1H), 4.88 (m, 0.6; H), 5.06 (q, 2H), 5.18 (q, 1H), 7.4 (m, 8H).

Preparation of AI: (R)-benzyl 4-((R)-hydroxy(4-methoxyphenyl)methyl)-2,2-dimethyloxazolidine-3-carboxylate

A solution of LiALH₄ (1 M, 20 mL, 20 mmol) was added dropwise to a cold (−15° C.) solution of (R)-benzyl 4-(methoxy(methyl)carbamoyl)-2,2-dimethyloxazolidine-3-carboxylate (12.2 g, 37.9 mmol) in THF (75 mL). The mixture was stirred for 30 min keeping the temperature below 0° C. A saturated solution of KHSO₄ (100 mL) was added slowly to the mixture and it was warmed to room temperature. The mixture was filtered and the solvent was removed to dryness. (R)-benzyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate was obtained as a clear oil (9.161 g, 92% yield) after purification by column chromatography (SiO₂, using a mixture of hexane/EtOAc).

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (m, 6H), 4.15 (m, 2H), 4.4 (m, 1H), 5.15, (s, 1H), 5.2 (m, 1H), 7.3 (m, 5H), 9.6 (m, 1H).

1,2-dibromoethane (0.2 mL) was added slowly to a hot (65° C.) solution of magnesium turnings (0.91 g, 37 mmol) in THF (14 mL), followed by the dropwise addition of a solution of 4-bromo anisole (4 mL, 32 mmol) in THF (14 mL). The mixture was refluxed for 2 hours and then cooled to room temperature. The grignard solution was added dropwise to a suspension of CuI (6.8 g, 36 mmol) in a mixture of Me₂S (20 mL)/THF (100 mL) at −78° C. The mixture was warmed slowly to −45° C. and stirred for 30 min keeping the temperature between −45 to −35° C. The mixture was cooled back to −78° C., and a solution of the Garner's aldehyde [(R)-benzyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate] (3.20 g, 12.6 mmol) in THF (15 mL) was added dropwise. The mixture was stirred at low temperature overnight (15 h, T max=10° C.). The reaction mixture was quenched with NH₄Cl (sat. 100 mL) and extracted with EtOAc (50 mL). The solvent was removed to dryness and the mixture was purified by column chromatography (SiO₂, using a mixture of hexane/EtOAc/acetone) and the product was obtained as a colorless oil (1.697 g, 36% yield).

Preparation of AII: benzyl (1R,2R)-1,3-dihydroxy-1-(4-methoxyphenyl)propan-2-ylcarbamate

A mixture of benzyl 4-(hydroxy-(4-methoxyphenyl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (1.679 g, 4.5 mmol) and amberlyst 15 (1.85 g) in MeOH (20 mL) was stirred at room temperature for 2 days. The mixture was centrifuged and the solid was washed with MeOH (2×40 mL). The solvent was removed to dryness and after purification by column chromatography (SiO₂ using a mixture of CH₂Cl₂/EtOAc) the product was obtained as a white solid (1.26 g, 84% yield).

Preparation of AIV: Synthesis of Compound 289: benzyl (1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-ylcarbamate

Mesityl chloride (0.28 mL, 3.6 mmol) was added slowly to a cold (−10° C.) solution of benzyl (1R,2R)-1,3-dihydroxy-1-(4-methoxyphenyl)propan-2-ylcarbamate (1.07 g, 3.23 mmol) in pyridine (1.5 mL). The mixture was stirred for 30 min and then pyrrolidine (2.7 mL, 33 mmol) was added slowly to the mixture. The mixture was heated to 45° C. for 6 hours and then the solvent was removed to dryness. After purification by column chromatography (SiO₂, using a mixture of CH₂Cl₂, MeOH, NH₄OH), the product was obtained as a clear oil (0.816 g, 66% yield).

Preparation of EVII: (1R,2R)-2-amino-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-1-ol as the amine was prepared by the procedures described below

A mixture of benzyl (1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-ylcarbamate (0.10 g, 0.26 mmol) and Pd/C (5%, 21 mg) in EtOH (1 mL)/HCl (1 M, 50 μL) was degassed and hydrogen gas was added. The mixture was hydrogenated at atmospheric pressure for two hours. The mixture was filtered over celite and the solvent was removed to dryness. The product was obtained as a colorless oil (63.5 mg, 85% yield).

Preparation of Compound 247: N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-3-(p-tolyloxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.3 (s, 3H), 2.65 (br, 6H), 2.85 (m, 2H), 3.75 (s, 3H), 4.1 (m, 2H), 4.25 (m, 1H), 5.05 (sd, 1H), 6.5 (br, 1H), 6.8 (m, 4H), 7.1 (d, 2H), 7.2 (d, 2H). M/Z for C₂₄H₃₂N₂O₄ [M−H]⁻=413.

Example 2E3 Preparation of Compound 251: N-((1R,2R-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.55 (br, 4H), 2.85 (m, 2H), 3.5 (s, 2H), 3.8 (s, 3H), 4.2 (m, 1H), 5.05 (sd, 1H), 5.8 (d, 1H), 6.8 (d, 2H), 7.1 (d, 2H), 7.2 (d, 2H), 7.55 (d, 2H). M/Z for C₂₃H₂₇F₃N₂O₃ [M−H]⁻=437.

Example 2E4 Preparation of Compound 5: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)benzo[b]thiophene-2-carboxamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 4H), 3.0 (m, 2H), 4.25 (s, 4H), 4.45 (m, 1H), 5.05 (sd, 1H), 6.6 (br, 1H), 6.85 (s, 2H), 6.95 (s, 1H), 7.4 (m, 2H), 7.7 (s, 1H), 7.85 (m, 2H). M/Z for C₂₄H₂₆N₂O₄S [M−H]⁻=439.

Example 2E5 Preparation of Compound 11: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(phenylthio)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.8 (br, 2H), 3.6 (q, 2H), 4.1.5 (m, 1H), 4.2 (s, 4H), 5.9 (sd, 1H), 6.7 (m, 2H), 6.8 (s, 1H), 7.2 (m, 7H). M/Z for C₂₃H₂₈N₂O₄S [M−H]⁻=429.

Example 2E6 Preparation of Compound 12: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)biphenyl-4-carboxamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 4H), 3.0 (m, 2H), 4.25 (s, 4H), 4.4 (br, 1H), 5.05 (sd, 1H), 6.6 (sd, 1H), 6.85 (m, 2H), 6.95 (s, 1H), 7.45 (m, 3H), 7.6 (m, 4H), 7.75 (m, 2H). M/Z for C₂₈H₃₀N₂O₄ [M−H]⁻=459.

Example 2E7 Preparation of Compound 19: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)benzo[b]thiophene-5-carboxamide

¹H NMR (d₆-dmso, 400 mHz, ppm); 1.6 (br, 4H), 2.4 (br, 5H), 2.65 (m, 1H), 4.15 (s, 4H), 4.25 (m, 1H), 4.75 (sd, 1H), 5.6 (br, 1H), 6.7 (m, 3H), 7.5 (sd, 1H), 7.7 (sd, 1H), 7.8 (sd, 1H), 7.85 (sd, 1H), 8.0 (sd, 1H), 8.2 (s, 1H). M/Z for C₂₄H₂₆N₂O₄S [M−H]⁻=439.

Example 2E8 Preparation of Compound 23: 2-(biphenyl-4-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.8 (d, 2H), 3.55 (s, 2H), 4.2 (m, 5H), 4.85 (sd, 1H), 5.95 (br, 1H), 6.6 (m, 1H), 6.75 (m, 2H), 7.2 (sd, 2H), 7.4 (m, 1H), 7.5 (st, 2H), 7.6 (m, 4H). M/Z for C₂₉H₃₂N₂O₄ [M−H]⁻=473.

Example 2E9 Preparation of Compound 24: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-phenoxyphenyl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.6 (br, 4H), 2.8 (sd, 2H), 3.45 (s, 2H), 4.15 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.9 (br, 1H), 6.6 (m, 1H), 6.7 (s, 1H), 6.8 (m, 1H), 7.15 (m, 7H), 7.4 (m, 2H). M/Z for C₂₉H₃₂N₂O₅ [M−H]⁻=489.

Example 2E10 Preparation of Compound 25: (S)—N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-hydroxy-3-phenylpropanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.65 (br, 7H), 3.1 (dd, 2H), 4.2 (m, 6H), 4.8 (sd, 1H), 6.6 (m, 1H), 6.8 (m, 3H), 7.3 (m, 5H). M/Z for C₂₄H₃₀N₂O₅ [M−H]⁻=427.

Example 2E11 Preparation of Compound 27: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-phenoxypropanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 6H), 2.9 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.45 (m, 1H), 6.75 (s, 1H), 6.85 (m, 3H), 6.95 (t, 1H), 7.2 (m, 3H). M/Z for C₂₄H30N₂O₅ [M−H]⁻=427.

Example 2E12 Preparation of Compound 31: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-phenylacetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.8 (br, 4H), 3.0 (m, 2H), 4.2 (s, 4H), 4.3 (m, 1H), 5.05 (sd, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.35 (m, 1H), 7.45 (t, 2H), 7.6 (t, 1H) 8.2 (d, 2H). M/Z for C₂₃H₂₆N₂O₅ [M−H]⁻=411.

Example 2E13 Preparation of Compound 32: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(phenylthio)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.4 (t, 2H), 2.7 (br, 4H), 2.8 (m, 2H), 3.1 (m, 2H), 4.2 (m, 5H), 4.9 (sd, 1H), 5.95 (br, 1H), 6.8 (m, 3H), 7.2 (m, 1H), 7.3 (m, 3H). M/Z for C₂₄H₃₀N₂O₄S [M−H]⁻=443.

Example 2E14 Preparation of Compound 35: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-o-tolylacetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.1 (s, 3H), 2.5 (br, 4H), 2.75 (m, 2H), 3.5 (s, 2H), 4.1 (m, 1H), 4.25 (s, 4H), 4.8 (sd, 1H), 5.75 (br, 1H), 6.5 (d, 1H), 6.65 (s, 1H), 6.75 (d, 1H), 7.1 (d, 1H), 7.2 (m, 3H). M/Z for C₂₄H₃₀N₂O₄ [M−H]⁻=411.

Example 2E15 Preparation of Compound 36: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-m-tolylacetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.35 (s, 3H), 2.5 (br, 4H), 2.75 (m, 2H), 3.45 (s, 2H), 4.1 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H), 6.55 (d, 1H), 6.75 (m, 2H), 6.9 (d, 2H), 7.1 (sd, 1H), 7.2 (m, 1H). M/Z for C₂₄H₃₀N₂O₄ [M−H]⁻=411.

Example 2E16 Preparation of Compound 39: 2-(benzylthio)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 4H), 2.9 (m, 2H), 3.0 (m, 2H), 3.3 (d, 1H), 3.55 (d, 1H), 4.2 (m, 5H), 5.05 (sd, 1H), 6.85 (s, 2H), 6.9 (s, 1H), 7.1 (sd, 2H), 7.3 (m, 3H). M/Z for C₂₄H₃₀N₂O₄S [M−H]⁻=443.

Example 2E17 Preparation of Compound 47: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(pyridin-3-yl)phenyl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.6 (br, 4H), 2.8 (sd, 2H), 3.55 (s, 2H), 4.15 (m, 1H), 4.2 (s, 4H), 4.85 (sd, 1H), 5.85 (br, 1H), 6.6 (d, 1H), 6.75 (m, 2H), 7.25 (d, 3H), 7.4 (m, 1H), 7.6 (sd, 2H), 7.9 (sd, 1H), 8.6 (sd, 1H), 8.85 (s, 1H). M/Z for C₂₈H₃₁N₃O₄ [M−H]⁻=474.

Example 2E18 Preparation of Compound 48: 2-(4′-chlorobiphenyl-4-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.55 (br, 4H), 2.8 (sd, 2H), 3.55 (s, 2H), 4.15 (m, 1H), 4.2 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H), 6.6 (d, 1H), 6.75 (m, 2H), 7.2 (d, 2H), 7.4 (m, 2H), 7.55 (sd, 4H). M/Z for C₂₉H₃₁ClN₂O₄ [M−H]⁻=508.

Example 2E19 Preparation of Compound 51: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3-(trifluoromethyl)phenyl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.55 (br, 4H), 2.8 (sd, 2H), 3.55 (s, 2H), 4.15 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H), 6.6 (d, 1H), 6.75 (m, 2H), 7.35 (d, 1H), 7.45 (m, 2H), 7.55 (sd, 1H). M/Z for C₂₄H₂₇F₃N₂O₄ [M−H]⁻=465.

Example 2E20 Preparation of Compound 53: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3-fluorophenyl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.55 (br, 4H), 2.8 (sd, 2H), 3.50 (s, 2H), 4.15 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H), 6.6 (d, 1H), 6.75 (m, 1H), 6.8 (d, 1H), 6.85 (d, 1H), 6.9 (d, 1H), 7.0 (t, 1H), 7.3 (sq, 1H), M/Z for C₂₃H₂₇FN₂O₄ [M−H]⁻=415.

Example 2E21 Preparation of Compound 54: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(3-methoxyphenoxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.65 (br, 6H), 2.85 (m, 2H), 3.80 (s, 3H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.45 (m, 4H), 6.75 (s, 2H), 6.85 (s, 1H), 7.2 (t, 1H). M/Z for C₂₅H₃₂N₂O₆ [M−H]⁻=457.

Example 2E22 Preparation of Compound 55: 3-(2,5-dichlorophenoxy)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.65 (br, 6H), 2.8 (m, 2H), 4.1 (m, 1H), 4.25 (m, 6H), 4.95 (sd, 1H), 6.3 (br, 1H), 6.75 (s, 2H), 6.8 (s, 1H), 6.9 (m, 2H), 7.25 (m, 1H). M/Z for C₂₄H₂₈Cl₂N₂O₅ [M−H]⁻=496.

Example 2E23 Preparation of Compound 57: 3-(4-chlorophenoxy)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.8 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.3 (br, 1H), 6.8 (m, 5H), 7.2 (m, 2H). M/Z for C₂₄H₂₉ClN₂O₅ [M−H]⁻=461.

Example 2E24 Preparation of Compound 58: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-fluorophenoxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.8 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.4 (br, 1H), 6.8 (m, 5H), 7.0 (m, 2H). M/Z for C₂₄H₂₉FN₂O₅ [M−H]⁻=445.

Example 2E25 Preparation of Compound 59: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(3-tolyloxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.3 (s, 3H), 2.65 (br, 6H), 2.8 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.45 (br, 1H), 6.75 (m, 4H), 6.85 (s, 1H), 7.1 (m, 2H). M/Z for C₂₅H₃₂N₂O₅ [M−H]⁻=441.

Example 2E26 Preparation of Compound 60: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(2-fluorophenoxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.75 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.35 (br, 1H), 6.7 (s, 2H), 6.85 (s, 1H), 6.95 (m, 2H), 7.05 (m, 2H). M/Z for C₂₄H₂₉FN₂O₅ [M−H]⁻=445.

Example 2E27 Preparation of Compound 61: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.75 (m, 2H), 3.8 (s, 3H), 4.1 (m, 2H), 4.2 (br, 5H), 4.95 (sd, 1H), 6.45 (br, 1H), 6.8 (m, 7H). M/Z for C₅H₃₂N₂O₆ [M−H]⁻=457.

Example 2E28 Preparation of Compound 188: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-ethylphenoxy)propanamide(2R,3R)-2,3-dihydroxysuccinate

¹H NMR (D₂O, 400 mHz, ppm); 0.93 (t, 3H), 1.75 (br, 2H), 1.86 (br, 2H), 2.35 (q, 2H), 2.4 (br, 2H), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 2H), 3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.6 (m, 5H), 7.0 (d, 2H). M/Z for C₂₆H₃₄N₂O₅.C₄H₆O₆ [M−H]⁻=454.

Example 2E29 Preparation of Compound 189: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-propionylphenoxy)propanamide(2R,3R)-2,3-dihydroxysuccinate

¹H NMR (D₂O, 400 mHz, ppm); 0.93 (t, 3H), 1.75 (br, 2H), 1.86 (br, 2H), 2.45 (br, 2H), 2.8 (q, 2H), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 2H), 3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.5 (d, 1H), 6.5 (d, 2H), 6.7 (d, 2H), 7.7 (d, 2H). M/Z for C₂₇H₃₄N₂O₆.C₄H₆O₆ [M−H]⁻=483.

Example 2E30 Preparation of Compound 193: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(3-oxobutyl)phenoxy)propanamide(2R,3R)-2,3-dihydroxysuccinate

¹H NMR (D₂O, 400 mHz, ppm); 1.75 (br, 2H), 1.86 (br, 2H), 1.94 (s, 3H), 2.45 (br, 2H), 2.6 (m, 4H), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 2H), 3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.6 (m, 5H), 7.0 (d, 2H). M/Z for C₂₈H₃₆N₂O₆.C₄H₆O₆ [M−H]⁻=497.

Example 2E31 Preparation of Compound 202: N-((1R, R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(2-methoxyethyl)phenoxy)propanamide(2R, R)-2,3-dihydroxysuccinate

¹H NMR (D₂O, 400 mHz, ppm); 1.75 (br, 2H), 1.86 (br, 2H), 2.45 (br, 2H), 2.62 (t, 2H), 2.9 (br, 2H), 3.1 (s, 3H), 3.25 (m, 2H), 3.4 (br, 4H), 3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.6 (m, 5H), 7.0 (d, 2H). M/Z for C₂₇H₃₆N₂O₆.C₄H₆O₆ [M−H]⁻=485.

Example 2E32 Preparation of Compound 63: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3′-methoxybiphenyl-4-yl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.75 (m, 2H), 3.5 (br, 2H), 3.9 (sd, 3H), 4.2 (m, 5H), 4.95 (sd, 1H), 5.9 (br, 1H), 6.5-7.6 (m, 11H). M/Z for C₃₀H₃₄N₂O₅ [M−H]⁻=503.

Example 2E33 Preparation of Compound 127: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(4-ethoxyphenyl)-4-oxobutanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.4 (t, 3H), 1.8 (br, 4H), 2.7 (br, 6H), 3.2 (m, 2H), 4.05 (q, 2H), 4.2 (m, 2H), 4.25 (m, 5H), 4.95 (sd, 1H), 6.05 (br, 1H), 6.9 (m, 5H), 7.95 (d, 2H). M/Z for C₂₇H₃₄N₂O₆ [M−H]⁻=483.

Example 2E34 Preparation of Compound 154: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(4-methoxyphenyl)-4-oxobutanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 6H), 3.2 (m, 1H), 3.45 (s, 3H), 3.9 (s, 3H), 4.2 (m, 5H), 4.95 (sd, 1H), 6.05 (br, 1H), 6.9 (m, 5H), 7.95 (d, 2H). M/Z for C₂₆H₃₂N₂O₆ [M−H]⁻=469.

Example 2E35 Preparation of Compound 181: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-isopropoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.4 (d, 6H), 1.8 (br, 8H), 2.15 (br, 2H), 2.8 (br, 10H), 4.25 (m, 5H), 4.65 (m, 1H), 4.95 (sd, 1H), 6.05 (br, 1H), 6.9 (m, 5H), 7.95 (d, 2H). M/Z for C₃₀H₄₀N₂O₆ [M−H]⁻=525.

Example 2E36 Preparation of Compound 191: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-methoxyphenyl)-5-oxopentanamide(2R,3R)-2,3-dihydroxysuccinate

¹H NMR (D₂O, 400 mHz, ppm); 1.40 (br, 1H), 1.53 (br, 1H), 1.75 (br, 2H), 1.91 (br, 2H), 1.98 (m, 1H), 2.15 (m, 1H) 2.45 (m, 2H), 2.95 (m, 2H), 3.35 (dd, 2H), 3.4 (m, 2H), 3.68 (br, 5H), 3.77 (br, 2H), 4.3 (br, 3H), 4.68 (br, 1H), 6.47 (d, 1H), 6.65 (d, 2H), 6.85 (d, 2H), 7.63 (d, 2H). M/Z for C₂₇H₃₄N₂O₆.C₄H₆O₆ [M−H]=483.

Example 2E37 Preparation of Compound 265: N-((1R,2R)-1-(benzo[δ][1,3]dioxol-5-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-isopropoxyphenyl)-5-oxopentanamide(2S,3S)-2,3-dihydroxysuccinate

¹H NMR (400 MHz, CD₃OD) δ 1.30 (sd, 6H), 1.70-1.85 (m, 2H), 2.04 (br, 4H), 2.09-2.26 (m, 2H), 2.64-2.82 (m, 2H), 3.31-3.48 (m, 5H), 4.37 (s, 2H), 4.43 (br, 1H), 4.68 (m, 1H), 4.71 (sd, 1H), 5.76 (s, 2H), 6.66 (d, 1H), 6.82-6.95 (m, 4H), 7.84 (d, 2H); MS for C₂₈H₃₆N₂O₆.C₄H₆O₆: [M−H]⁻ 645.

Example 2E38 Preparation of Compound 267: N-((1R,2R)-1-(benzo[β][1,3]dioxol-5-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide(2S,3S)-2,3-dihydroxysuccinate

¹H NMR (400 MHz, CD₃OD) δ 1.49 (br, 4H), 2.03 (br, 4H), 2.89 (t, 2H), 3.33-3.46 (m, 6H), 3.84 (s, 3H), 4.37 (s, 2H), 4.43 (d, 1H), 4.76 (br, 1H), 5.81 (s, 2H), 6.68 (d, 1H), 6.81 (d, 1H), 6.88 (s, 1H), 6.96 (d, 2H), 7.92 (d, 2H); MS for C₂₇H₃₄N₂O₆.C₄H₆O₆: [M−H]⁻ 633.

Example 2E39 Preparation of Compound 268: N-((1R,2R)-1-(benzo[δ][1,3]dioxol-5-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-isopropoxyphenyl)-7-oxoheptanamide(2S,3S)-2,3-dihydroxysuccinate

¹H NMR (400 MHz, CD₃OD) δ 1.15-1.18 (m, 2H), 1.30 (d, 6H), 1.40-1.45 (m, 2H), 1.57-1.65 (m, 2H), 2.03 (br, 4H), 2.12-2.17 (m, 2H), 2.88 (t, 2H), 3.33-3.48 (m, 5H), 4.38 (s, 2H), 4.42 (d, 1H), 4.67 (m, 1H), 4.78 (d, 1H), 5.83 (d, 2H), 6.71 (d, 1H), 6.82 (d, 1H), 6.89 (s, 1H), 6.92 (d, 2H), 7.90 (d, 2H); MS for C₃₀H₄₀N₂O₆.O₄H₆O₆: [M−H]⁻ 675.

Example 2E40 Preparation of Compound 197: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-1)propan-2-yl)-4-(4-methoxyphenoxy)butanamide(2S,3S)-2,3-dihydroxysuccinate

¹H NMR (400 MHz, CD₃OD) δ 1.78-1.91 (m, 2H), 2.00 (br, 4H), 2.32 (t, 2H), 3.33-3.47 (m, 6H), 3.69 (s, 3H), 3.72 (t, 2H), 4.11 (br, 4H), 4.37 (s, 2H), 4.41 (d, 1H), 4.72 (d, 1H), 6.69-6.86 (m, 7H); MS for C₂₆H₃₄N₂O₆.C₄H₆O₆: [M−H]⁻ 621.

Example 2E41 Preparation of Compound 187: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(3-methylbutanoyl)phenoxy)propanamide(2S,3S)-2,3-dihydroxysuccinate

¹H NMR (400 MHz, CD₃OD) δ 0.95 (d, 6H), 2.00 (br, 4H), 2.17 (m, 2H), 2.66 (t, 2H), 2.78 (d, 2H), 3.34-3.44 (m, 5H), 4.12-4.17 (m, 6H), 4.40 (s, 2H), 4.45 (d, 1H), 4.73 (sd, 1H), 6.67 (d, 1H), 6.79 (d, 1H), 6.86 (s, 1H), 6.93 (d, 2H), 7.91 (d, 2H); MS for C₂₉H₃₈N₂O₆.C₄H₆O₆: [M−H]⁻ 661.

Example 2E42 Preparation of Compound 83: 2-(4-chlorophenoxy)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

¹H NMR (400 MHz, CDCl₃) δ 1.76 (br, 4H), 2.63 (br, 4H), 2.78 (dd, 1H), 2.89 (dd, 1H), 4.24 (s, 4H), 4.27 (br, 1H), 4.36 (q, 2H), 4.94 (d, 1H), 6.71 (d, 1H), 6.77-6.82 (m, 4H), 6.86 (d, 1H), 7.24 (s, 1H); MS for C₂₃H₂₇ClN₂O₅: [M−H]⁻ 447.

Example 2E43 Preparation of Compound 87: 2-(3,4-dichlorophenoxy)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

¹H NMR (400 MHz, CDCl₃) δ 1.78 (br, 4H), 2.67 (br, 4H), 2.79 (dd, 1H), 2.92 (dd, 1H), 4.25 (br, s, 5H), 4.35 (q, 2H), 4.95 (d, 1H), 6.71-6.84 (m, 5H), 7.01 (d, 1H), 7.34 (d, 1H); MS for C₂₃H₂₆Cl₂N₂O₅: [M−H]⁻ 482.

Example 2E44 Preparation of Compound 86: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3-phenoxyphenyl)acetamide

¹H NMR (400 MHz, CDCl₃) δ 1.72 (br, 4H), 2.57 (br, 4H), 2.75-2.80 (m, 2H), 3.45 (s, 2H), 4.11-4.13 (m, 1H), 4.23 (s, 4H), 4.84 (d, 1H), 5.86 (d, 1H), 6.55 (dd, 1H), 6.71 (d, 1H), 6.74 (d, 1H), 6.80 (br, 1H), 6.85 (dd, 1H), 6.92 (dd, 1H), 6.98 (d, 1H), 7.14 (t, 1H), 7.28-7.36 (m, 2H); MS for C₂₉H₃₂N₂O₅: [M−H]⁻ 489.

Example 2E45 Preparation of Compound 280: 2-(3,4-difluorophenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-1)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

¹H NMR (400 MHz, CDCl₃) δ 1.80 (br, 4H, 2.68 (br, 4H), 2.84 (d, 2H), 3.45 (s, 2H), 4.17 (m, 1H), 4.25 (s, 4H), 4.88 (d, 1H), 5.88 (d, 1H), 6.65 (d, 1H), 6.79 (d, 1H), 6.95 (m, 1H), 6.95 (t, 1H), 7.13 (q, 1H); MS for C₂₃H₂₆F₂N₂O₄: [M−H]⁻ 434.

Example 2E46 Preparation of Compound 103: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide

¹H NMR (400 MHz, CDCl₃) δ 1.65 (br, 4H), 2.48 (br, 4H), 2.69 (d, 2H), 3.40 (s, 2H), 4.08 (m, 1H), 4.17 (s, 4H), 4.80 (s, 1H), 5.84 (t, 1H), 6.55 (d, 1H), 6.66 (s, 1H), 6.70 (d, 1H), 7.10 (t, 3H); MS for C₂₄H₂₇F₃N₂O₅: [M−H]⁻ 481.

Example 2E47 Preparation of Compound 90: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 1.82 (br, 4H), 2.73-2.81 (m, 4H), 2.89-2.93 (m, 1H), 3.02-3.07 (m, 1H), 4.23 (s, 4H), 4.41 (br, 1H), 5.07 (s, 1H), 5.30 (d, 1H), 6.74 (s, 1H), 6.83 (t, 2H), 6.90 (s, 1H), 7.12-7.14 (m, 2H), 7.47 (d, 1H), 7.52 (d, 1H); MS for C₂₃H₂₅N₃O₅S: [M−H]⁻ 456.

Example 2E48 Preparation of Compound 92: 3-(3-chloro-4-methoxyphenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)propanamide

¹H NMR (400 MHz, CDCl₃) δ 1.77 (br, 4H), 2.38 (t, 2H), 2.60 (br, 4H), 2.8 (m, 4H), 3.86 (s, 3H), 4.20 (br, 1H), 4.24 (s, 4H), 4.87 (s, 1H), 5.80 (d, 1H), 6.66 (d, 1H), 6.8 (m, 3H), 7.00 (d, 1H), 7.18 (s, 1H); MS for C₂₅H₃₁ClN₂O₅: [M−H]⁻ 475.

Example 2E49 Preparation of Compound 96: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-trifluoromethyl)phenyl)propanamide

¹H NMR (400 MHz, CDCl₃) δ 1.73 (br, 4H), 2.4 (m, 2H), 2.53 (m, 4H), 2.7 (m, 2H), 2.90-2.97 (m, 2H), 4.17 (br, 1H), 4.23 (s, 4H), 4.89 (s, 1H), 5.83 (br, 1H), 6.68 (d, 1H), 6.79 (d, 2H), 7.24 (d, 2H), 7.50 (d, 2H); MS for C₂₅H₂₉F₃N₂O₅: [M−H]⁻ 479.

Example 2E50 Preparation of Compound 101: 4-(benzo[d]thiazol-2-yl)-N-(1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)butanamide

¹H NMR (400 MHz, CDCl₃) δ 1.77 (br, 4H), 2.10-2.15 (m, 2H), 2.24-2.27 (m, 2H), 2.64-2.67 (m, 4H), 2.79-2.83 (m, 2H), 3.02 (t, 2H), 4.18 (s, 4H), 4.26 (br, 1H), 4.92 (d, 1H), 6.12 (br, 1H), 6.75-6.81 (m, 2H), 6.86 (s, 1H), 7.37 (1, 1H), 7.45 (t, 1H), 7.85 (d, 1H), 7.92 (d, 1H); MS for C₂₆H₃₁N₃O₄S: [M−H]⁻ 482.

Example 2E51 Preparation of Compound 102: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(2,3-dihydrobenzo[β][1,4]dioxine-6-sulfonamido)hexanamide

¹H NMR (400 MHz, CDCl₃) δ 1.15-1.20 (m, 2H), 1.38-1.50 (m, 4H), 1.77 (br, 4H), 2.08 (q, 2H), 2.63-2.66 (m, 4H), 2.79 (d, 2H), 2.87 (t, 2H), 4.2 (m, 9H), 4.91 (br, 1H), 5.93 (br, 1H), 6.77 (q, 2H), 6.84 (s, 1H), 6.93 (d, 1H), 7.31 (d, 1H), 7.37 (s, 1H); MS for C₂₉H₃₉N₃O₈S: [M−H]⁻ 590.

Example 2E52 Preparation of Compound 104: N-(5-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-ylamino)-5-oxopentyl)benzamide

¹H NMR (400 MHz, CDCl₃) δ 1.47-1.52 (m, 2H), 1.59-1.69 (m, 2H), 1.77 (br, 4H), 2.15-2.21 (m, 2H), 2.62-2.65 (m, 4H), 2.81 (br, 2H), 3.30-3.42 (m, 2H), 4.19-4.23 (m, 5H), 4.94 (br, 1H), 5.98 (br, 1H), 6.76 (br, 1H), 6.78-6.86 (m, 3H), 7.40-7.50 (m, 3H), 7.80 (d, 2H); MS for C₂₇H₃₅N₃O₅: [M−H]⁻ 482.

Example 2E53 Preparation of Compound 281: N1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-N5-(thiazol-2-yl)glutaramide

¹H NMR (400 MHz, CDCl₃) δ 1.74 (br, 4H), 1.97-2.03 (m, 2H), 2.20-2.26 (m, 2H), 2.40-2.45 (m, 2H), 2.64-2.68 (m, 5H), 2.88 (m 1H), 4.20 (s, 4H), 4.26-4.29 (m, 1H), 4.83 (d, 1H), 6.12 (br, 1H), 6.74-6.79 (m, 2H), 6.85 (s, 1H), 6.95 (d, 1H), 7.41 (d, 1H); MS for C₂₃H₃₀N₄O₅S: [M−H]⁻ 475.

Example 2E54 Preparation of Compound 282: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(3,4-dimethoxyphenyl)-5-oxopentanamide

¹H NMR (400 MHz, CDCl₃) δ 1.76 (br, 4H), 1.92-2.00 (m, 2H), 2.21-2.26 (m, 2H), 2.60-2.65 (m, 4H), 2.70-2.95 (m, 4H), 3.93 (d, 6H), 4.17-4.23 (m, 5H), 4.90 (d, 1H), 5.96 (br, 1H), 6.75-6.79 (m, 2H), 6.85 (s, 1H), 6.87 (d, 1H), 7.50 (s, 1H), 7.55 (d, 1H); MS for C₂₈H₃₆N₂O₇: [M−H]⁻ 513.

Example 2E55 Preparation of Compound 283: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-oxo-5-p-tolylpentanamide

¹H NMR (400 MHz, CDCl₃) δ 1.77 (br, 4H), 1.96-2.02 (m, 2H), 2.21-2.26 (m, 2H), 2.40 (s, 3H), 2.63-2.80 (m, 4H), 2.82-2.95 (m, 4H), 4.18-4.23 (m, 5H), 4.91 (d, 1H), 5.94 (br, 1H), 6.74-6.77 (m, 2H), 6.85 (s, 1H), 7.26 (d, 2H), 7.81 (d, 2H); MS for C₂₇H₃₄N₂O₅: [M−H]⁻ 467.

Example 2E56 Preparation of Compound 113: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-oxo-5-phenylpentanamide

¹H NMR (400 MHz, CDCl₃) δ 1.76 (br, 4H), 1.95-2.01 (m, 2H), 2.22-2.25 (m, 2H), 2.62-2.63 (m, 4H), 2.78-2.95 (m, 4H), 4.17-4.22 (m, 5H), 4.91 (sd, 1H), 5.99 (br, 1H), 6.77 (st, 2H), 6.85 (s, 1H), 7.44-7.58 (m, 3H), 7.92 (d, 2H); MS for C₂₆H₃₂N₂O₅: [M−H]⁻ 453.

Example 2E57 Preparation of Compound 284: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-isopropoxyphenyl)-5-oxopentanamide

¹H NMR (400 MHz, CDCl₃) δ 1.36 (d, 6H), 1.75 (br, 4H), 1.90-2.02 (m, 2H), 2.20-2.25 (m, 2H), 2.60-2.66 (m, 4H), 2.70-2.86 (m, 4H), 4.17 (s, 4H), 4.22 (br, 1H), 4.62-4.65 (m, 1H), 4.89 (sd, 1H), 6.07 (d, 1H), 6.77 (s, 2H), 6.85 (s, 1H), 6.87 (d, 2H), 7.86 (d, 2H); MS for C₂₉H₃₈N₂O₆: [M−H]⁻ 511.

Example 2E58 Preparation of Compound 140: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxy-3,5-dimethylphenyl)-6-oxohexanamide

¹H NMR (400 MHz, CDCl₃) δ 1.61-1.63 (m, 4H), 1.77 (br, 4H), 2.16 (t, 2H), 2.32 (s, 6H), 2.61-2.67 (m, 4H), 2.74-2.89 (m, 2H), 2.91 (t, 2H), 3.75 (s, 3H), 4.21 (br, 5H), 4.90 (sd, 1H), 5.93 (br, 1H), 6.75-6.82 (m, 2H), 6.85 (sd, 1H), 7.61 (s, 2H); MS for C₃₀H₄₀N₂O₆: [M−H]⁻ 525.

Example 2E59 Preparation of Compound 141: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (400 MHz, CDCl₃) δ 1.62-1.64 (m, 4H), 1.76 (br, 4H), 2.17 (t, 2H), 2.61-2.65 (m, 4H), 2.72-2.79 (m, 2H), 2.89 (t, 2H), 3.86 (s, 3H), 4.20 (br, 5H), 4.89 (d, 1H), 6.01 (br, 1H), 6.77 (q, 2H), 6.85 (s, 1H), 6.91 (d, 2H), 7.90 (d, 2H); MS for C₂₈H₃₆N₂O₆: [M−H]⁻ 497.

Example 2E60 Preparation of Compound 155: 6-(4-tert-butylphenyl)-N-((1R,2R-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-oxohexanamide

¹H NMR (400 MHz, CDCl₃) δ 1.34 (s, 9H), 1.63-1.65 (m, 4H), 1.77 (br, 4H), 2.17 (t, 2H), 2.64-2.66 (br, 4H), 2.75 (dd, 1H), 2.2.81 (dd, 1H), 2.91 (t, 2H), 4.20 (br, 5H), 4.90 (d, 1H), 6.02 (br, 1H), 6.77-6.82 (q, 2H), 6.85 (d, 1H), 7.46 (d, 2H), 7.86 (d, 2H); MS for C₃₁H₄₂N₂O₅: [M−H]⁻ 523.

Example 2E61 Preparation of Compound 156: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-methoxyphenyl)-7-oxoheptanamide

¹H NMR (400 MHz, CDCl₃) δ 1.25-1.30 (m, 2H), 1.55-1.70 (m, 4H), 1.77 (br, 4H), 2.13 (t, 2H), 2.61-2.66 (m, 4H), 2.74-2.82 (m, 2H), 2.88 (t, 2H), 3.86 (s, 3H), 4.20 (br, 5H), 4.90 (d, 1H), 5.93 (br, 1H), 6.78 (q, 2H), 6.85 (s, 1H), 6.91 (d, 2H), 7.92 (d, 2H); MS for C₂₉H₃₈N₂O₆: [M−H]⁻ 511.

Example 2E62 Preparation of Compound 144: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-8-(4-methoxyphenyl)-8-oxooctanamide

¹H NMR (400 MHz, CDCl₃) δ 1.25-1.33 (m, 4H), 1.54 (m, 2H), 1.68 (t, 2H), 1.78 (br, 4H), 2.11 (br, 2H), 2.65 (br, 4H), 2.76-2.11 (m, 4H), 3.86 (s, 3H), 4.21 (br, 5H), 4.90 (br, 1H), 6.02 (d, 1H), 6.78-6.84 (m, 3H), 6.91 (d, 2H), 7.92 (d, 2H); MS for C₃₀H₄₀N₂O₆: [M−H]⁻ 525.

Example 2E63 Preparation of Compound 159: 7-(4-chlorophenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-oxoheptanamide

¹H NMR (400 MHz, CDCl₃) δ 1.26-1.37 (m, 2H), 1.57 (m, 2H), 1.68 (m, 2H), 1.77 (br, 4H), 2.13 (t, 2H), 2.62-2.65 (m, 4H), 2.76-2.82 (m, 2H), 2.90 (t, 2H), 4.20 (br, 5H), 4.90 (d, 1H), 5.93 (d, 1H), 6.78 (q, 2H), 6.85 (s, 1H), 7.42 (d, 2H), 7.87 (d, 2H); MS for C₂₈H₃₅ ClN₂O₅: [M−H]⁻ 515.

Example 2E64 Preparation of Compound 160: 7-(4-tert-butylphenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-oxoheptanamide

¹H NMR (400 MHz, CDCl₃) δ 1.27-1.34 (m, 11H), 1.56-1.71 (m, 4H), 1.77 (br, 4H), 2.13 (t, 2H), 2.63-2.66 (m, 4H), 2.76-2.819 (m, 2H), 2.91 (t, 2H), 4.20 (br, 5H), 4.90 (sd, 1H), 5.90 (d, 1H), 6.81 (q, 2H), 6.85 (s, 1H), 7.46 (d, 2H), 7.88 (d, 2H); MS for C₃₂H₄₄N₂O₅: [M−H]⁻ 537.

Example 2E65 Preparation of Compound 168: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-methoxyphenyl)-7-oxoheptanamide(2S,3S)-2,3-dihydroxysuccinate

¹H NMR (400 MHz, CD₃OD) δ 1.15-1.19 (m, 2H), 1.40-1.47 (m, 2H), 1.60 (m, 2H), 2.02 (br, 4H), 2.09-2.21 (m, 2H), 2.90 (t, 2H), 3.35-3.49 (m, 5H), 3.83 (s, 3H), 4.12 (br, 4H), 4.38 (s, 2H), 4.43 (m, 1H), 4.74 (sd, 1H), 6.71 (d, 1H), 6.79 (dq, 1H), 6.86 (sd, 1H), 6.96 (d, 2H), 7.92 (d, 2H); MS for C₂₉H₃₈N₂O₆.C₄H₆O₆: [M−H]⁻ 661.

Example 2E66 Preparation of Compound 162: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(4-isopropoxyphenyl)-4-oxobutanamide

¹H NMR (400 MHz, CDCl₃) δ 1.35 (d, 6H), 1.77 (br, 4H), 2.52-2.56 (m, 2H), 2.64-2.83 (m, 6H), 3.09-3.36 (m, 2H), 4.22 (br, 5H), 4.63-4.66 (m, 1H), 4.89 (sd, 1H), 6.13 (d, 1H), 6.78 (s, 2H), 6.88 (t, 3H), 7.90 (d, 2H); MS for C₂₈H₃₆N₂O₆: [M−H]⁻ 497.

Example 2E67 Preparation of Compound 176: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-oxo-4-(4-(trifluoromethyl)phenyl)butanamide(2S,3S)-2,3-dihydroxysuccinate

¹H NMR (400 MHz, CD₃OD) δ 2.08 (br, 4H), 2.54-2.72 (m, 2H), 3.24-3.48 (m, 6H), 4.19 (s, 4H), 4.29 (m, 4H), 4.74 (sd, 1H), 6.76 (d, 1H), 6.86 (d, 1H), 6.92 (s, 1H), 7.81 (d, 2H), 8.13 (d, 2H); MS for C₂₆H₂₉F₃N₂O₅.C₄H₆O₆: [M−H]⁻ 657.

Example 2E68 Preparation of Compound 65 (Genz-528152-1): 2-(3′-chlorobiphenyl-4-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

¹H NMR (400 MHz, CDCl₃) δ 1.70 (br, 4H), 2.54 (br, 4H), 2.72-2.81 (m, 2H), 3.53 (s, 2H), 4.12-4.23 (m, 5H), 4.85 (d, 1H), 5.82 (d, 1H), 6.58 (dd, 1H), 6.70 (sd, 1H), 6.73 (d, 1H), 7.19 (d, 1H), 7.32-7.34 (m, 1H), 7.38 (t, 1H), 7.46-7.49 (m, 1H), 7.52 (d, 2H), 7.59 (d, 1H); C₂₉H₃₁ClN₂O₄: [M−H]⁻ 507.

Example 2E69 Preparation of Compound 262: N-[2-Hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyl]-3-(4-methoxy-phenoxy)-propionamide

¹H NMR (CDCl₃ 400 mHz, ppm); 1.75 (m, 4H), 2.55 (m, 2H), 2.65 (m, 4H), 2.85 (m, 2H), 3.8 (s, 6H), 4.1 (m, 2H), 4.25 (m, 1H), 5.0 (d, 1H), 6.5 (br, d, 1H), 6.8 (m, 4H), 7.25 (m, 4H). M/Z for C₂₄H₃₂N₂O₅ [M−H]⁻ 429.

Example 2E70 Preparation of Compound 270: 5-(4-Isopropoxy-phenyl)-5-oxo-pentanoic acid [2-hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyl]amide

¹H NMR (CDCl₃ 400 mHz, ppm); 1.4 (d, 6H), 1.8 (m, 4H), 2.0 (m, 2H), 2.2 (m, 2H), 2.6 (m, 4H), 2.8 (m, 4H), 3.75 (s, 3H), 4.25 (m, 1H), 4.65 (m, 1H), 5.0 (d, 1H), 5.95 (br. d, 1H), 6.85 (m, 4H), 7.25 (m, 2H), 7.9 (m, 2H). M/Z for C₂₄H₃₂N₂O₅ [M−H]⁺ 483.3.

Example 2E71 Preparation of Compound 285: 7-(4-Methoxy-phenyl)-7-oxo-heptanoic acid [2-hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyl]-amide

¹H NMR (CDCl₃ 400 mHz, ppm); 1.25 (m, 2H), 1.6 (m, 4H), 1.8 (m, 4H), 2.15 (m, 2H), 2.65 (m, 4H), 2.85 (m, 4H), 3.75 (s, 3H), 3.9 (s, 3H), 4.2 (m, 1H), 5.0 (d, 1H), 5.9 (br. d, 1H), 6.85 (d, 2H), 6.95 (d, 2H), 7.2 (d, 2H), 7.95 (d, 2H). M/Z for C₂₄H₃₂N₂O₅ [M−H]⁺ 483.3

Example 2E72 Preparation of Compound 262: N-[2-Hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyl]-3-(4-methoxy-phenoxy)-propionamide

¹H NMR (CDCl₃ 400 mHz, ppm); 1.75 (m, 4H), 2.55 (m, 2H), 2.65 (m, 4H), 2.85 (m, 2H), 3.8 (s, 6H), 4.1 (m, 2H), 4.25 (m, 1H), 5.0 (d, 1H), 6.5 (br. d, 1H), 6.8 (m, 4H), 7.25 (m, 4H). M/Z for C₂₄H₃₂N₂O₅ [M−H]⁺ 429.

Example 2E73 Preparation of Compound 270:5 (4-Isopropoxy phenyl-5-oxo-pentanoic acid [2-hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyl]amide

¹H NMR (CDCl₃ 400 mHz, ppm); 1.4 (d, 6H), 1.8 (m, 4H), 2.0 (m, 2H), 2.2 (m, 2H), 2.6 (m, 4H), 2.8 (m, 4H), 3.75 (s, 3H), 4.25 (m, 1H), 4.65 (m, 1H), 5.0 (d, 1H), 5.95 (br. d, 1H), 6.85 (m, 4H), 7.25 (m, 2H), 7.9 (m, 2H). M/Z for C₂₄H₃₂N₂O₅ [M−H]⁺ 483.3.

Example 2E74 Preparation of Compound 305

¹H NMR (CDCl₃ 400 mHz, ppm); 1.25 (m, 14H), 1.6 (m, 4H), 1.8 (m, 4H), 2.1 (t, 2H), 2.6 (t, 2H), 2.8 (m, 6H), 4.2 (m, 5H), 4.9 (d, 1H), 6.0 (br d, 1H), 6.8 (m, 3H), 7.2 (m, 1H), 7.5 (m, 1H), 8.4 (m, 2H). M/Z for C₂₄H₃₂N₂O₅ [M−H]⁺538.

Example 2E75 Preparation of Compound 320: Octanoic acid [2-hydroxy-2(4-methoxy-phenyl)-1-Pyrrolidin1-ylmethyl-ethyl]-amide

¹H NMR (CDCl₃ 400 mHz, ppm); 0.9 (t, 3H), 1.2 (m, 8H), 1.5 (m, 2H), 1.8 (m, 4H), 2.1 (t, 2H), 2.65 (m, 4H), 2.8 (d, 2H), 3.8 (s, 3H), 4.2 (m, 1H), 4.95 (d, 1H), 5.9 (br d, 1H), 6.9 (2 s, 2H), 7.25 (m, 2H). M/Z for C₂₂H₃₆N₂O₃ [M−H]⁺ 377.4.

Example 2E76 Preparation of Cyclic Amide Analogs

Cyclic amide analogs were prepared according to Scheme 6. 2-Amino-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-pyrrolidin-1-yl-propan-1-ol was prepared according to the preparation of intermediate 4 of U.S. Pat. No. 6,855,830 B2. This amine was coupled with various nitriles in potassium carbonate and glycerol, under an atmosphere of nitrogen, for example, at 115° C. for 18 hours. Compound 323 characterized by the following structural formula was prepared by following Scheme 6. Compound 323 was purified by column chromatography using a mixture of methanol and methylene chloride.

¹H NMR (CDCl₃ 400 mHz, ppm); 0.95 (t, 3H), 1.35 (m, 2H), 1.6 (m, 2H), 1.8 (m, 4H), 2.7 (m, 6H), 2.8 (m, 2H), 4.2 (m, 5H), 5.4 (d, 1H), 6.85 (m, 3H), 7.2 (m, 2H), 7.9 (d, 2H). M/Z for C₂₄H₃₂N₂O₃ [M−H]⁺ 421.54.

Example 2E77 Preparation of N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-(2-methoxyethoxy)phenyl)-5-oxopentanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.25 (t, 3H), 1.8 (br, 4H), 1.95 (m, 2H), 2.05 (t, 3H), 2.25 (m, 2H), 3.65 (m, 4H), 2.90 (m, 4H), 3.4 (s, 4H), 3.8 (m, 2H), 4.15 (m, 9H), 4.95 (br, 1H), 5.95 (br, 1H), 6.88-6.95 (m, 5H), 7.9 (m, 2H). M/Z for C₂₉H₃₈N₂O₇ [M+H]=527.

Example 2E78 Preparation of N-((1R,2R)-1-(4-chlorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.76 (br, 4H), 2.52-2.57 (sq, 2H), 2.60-2.73 (br, 4H), 2.88-2.96 (st, 2H), 3.8 (s, 3H), 3.96-4.0 (m, 1H), 4.06-4.11 (1H), 4.21-4.24 (m, 1H), 5.07 (d, 1H), 6.57 (bd, 1H), 6.77-6.87 (sq, 4H), 7.20-7.27 (sd, 6H). M/Z for C₂₃H₂₉ClN₂O₄ [M+H]=433.

Example 2E79 Preparation of N-((1R,2R)-1-(4-chlorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.54-1.62 (br, 4H), 1.79 (br, 4H), 2.14 (t, 2H), 2.63-2.69 (br, 4H), 2.83-2.89 (m, 4H), 3.88 (s, 3H), 4.24 (br, 1H), 5.03 (d, 1H), 5.93 (d, 1H), 6.93 (d, 2H), 7.26-7.32 (m, 4H), 7.93 (d, 2H). M/Z for C₂₆H₃₃ClN₂O₄ [M+H]=473.

Example 2E80 Preparation of N-((1R,2R)-1-hydroxy-1-(4-methoxy-3-methylphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.77 (br, 4H), 1.91-2.0 (m, 2H), 2.18 (s, 3H), 2.2-2.25 (m, 2H), 2.62-2.69 (m, 4H), 2.77-2.89 (m, 4H), 3.75 (s, 3H), 3.88 (s, 3H), 4.23 (m, 1H), 4.96 (sd, 1H), 5.93 (br, 1H), 6.75 (br, 1H), 6.94 (d, 2H), 7.1 (br, 2H), 7.88 (m, 2H). M/Z for C₂₈H₃₈N₂O₅ [M+H]=483.

Example 2E81 Preparation of N-((1R,2R)-1-hydroxy-1-(4-methoxy-3-methylphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.73 (br, 4H), 2.20 (s, 3H), 2.55 (br, 4H), 2.81 (st, 2H), 3.46 (s, 2H), 3.82 (s, 3H), 4.15 (m, 1H), 4.92 (sd, 1H), 5.85 (br, 1H), 672 (d, 1H), 6.95 (sd, 1H), 7.00 (br, 1H), 7.2 (m, 4H). M/Z for C₂₄H₂₉F₃N₂O₄ [M+H]=467.

Example 2E82 Preparation of N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propan-2-yl)octanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 0.9 (t, 3H), 1.2 (m, 11H), 1.5 (bm, 8H), 1.8 (br, 4H), 2.1 (m, 2H), 2.65 (m, 4H), 2.90 (m, 2H), 4.2 (m, 1H), 5.05 (d, 1H), 5.85 (br, 1H), 7.2 (m, 3H). M/Z for C₂₃H₃₂F₄N₂O₄ [M+H]=477.

Example 2E83 Preparation of N-((1R,2R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.75 (br, 4H), 2.55 (br, 4H), 2.85 (m, 2H), 3.45 (s, 2H), 4.1 (m, 1H), 5.0 (d, 1H), 5.85 (br, 1H), 6.8-6.95 (3H), 7.1-7.20 (4H). M/Z for C₂₃H₂₃F₅N₂O₅ [M+H]=503.

Example 2E84 Preparation of N-((1R,2R)-1-hydroxy-1-(4-(2-phenoxyethoxy)phenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.6 (m, 4H), 1.8 (m, 4H), 2.15 (t, 2H), 2.7 (m, 4H), 2.85 (m, 4H), 3.8 (s, 3H), 4.25 (m, 1H), 4.3 (s, 3H), 5.0 (d, 1H), 5.95 (br, 1H), 6.9 (m, 7H), 7.2 (m, 4H), 7.95 (m, 2H). M/Z for C₃₄H₄₂N₂O₆ [M+H]=575.

Example 2E85 Preparation of N-((1R,2R)-1-(4-(cyclobutylmethoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.6 (br, 4H), 1.9 (m, 9H), 2.05 (m, 5H), 2.75-3.0 (m, 9H), 3.8 (m, 5H), 4.3 (m, 1H), 5.0 (m, 1H), 6.2 (br, 1H), 6.9 (m, 4H), 7.25 (m, 2H), 7.9 (m, 2H). M/Z for C₃₁H₄₂N₂O₅ [M+H]=523.

Example 2E86 Preparation of N-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.6 (m, 8H), 1.8 (m, 10H), 2.15 (t, 2H), 2.65 (m, 4H), 2.8 (d, 2H), 2.9 (m, 5H), 2.95 (s, 3H), 4.0 (t, 2H), 4.15 (m, 1H), 4.45 (t, 1H), 4.55 (t, 1H), 4.95 (br, 2H), 5.9 (br, 1H), 6.90 (m, 4H), 7.20 (m, 2H), 7.95 (m, 2H), 8.05 (br, 1H). M/Z for C₃₀H₁₁FN₂O₅ [M+H]=529.

Example 2E87 Preparation of N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(3-(p-tolyloxy)propoxy)phenyl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.65 (m, 4H), 1.8 (m, 4H), 2.15 (t, 2H), 2.25 (t, 2H), 2.3 (s, 3H), 2.65 (m, 4H), 2.8 (m, 2H), 2.9 (t, 2H), 3.85 (s, 3H), 4.15 (m, 4H), 4.25 (m, 1H), 4.95 (br, 1H), 6.85 (br, 1H), 6.8-6.95 (m, 6H), 7.05 (m, 2H), 7.2 (m, 2H), 7.95 (2H). M/Z for C₃₆H₄₆N₂O₆ [M+H]=603.

Example 2E88 Preparation of N-((1R,2R)-1-(4-butoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.0 (t, 3H), 1.5 (m, 2H), 1.65 (m, 4H), 1.8 (m, 6H), 2.15 (t, 2H), 2.65 (m, 4H0, 2.8 (m, 2H), 2.9 (t, 2H), 3.85 (s, 3H), 3.9 (t, 2H), 4.15 (m, 1H), 4.95 (br, 1H), 5.90 (br, 1H), 6.8-6.95 (m, 4H), 7.2 (br, 2H), 7.90 (br, 2H). M/Z for C₃₀H₄₂N₂O₅ [M+H]=511.

Example 2E89 Preparation of N-((1R,2R)-1-(4-(hexyloxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-(2-methoxyethoxy)phenyl)-5-oxopentanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 0.95 (t, 3H), 1.35 (m, 4H), 1.45 (m, 2H), 1.7 (m, 6H), 1.95 (m, 2H), 2.20 (m, 2H), 2.65 (m, 4H), 2.85 (m, 4H), 3.45 (s, 3H), 3.75 (m, 2H), 3.90 (t, 2H), 4.15 (m, 2H), 4.25 (m, 1H), 4.95 (m, 1H), 6.0 (br, 1H), 6.8 (m, 2H), 6.9 (m, 2H), 7.2 (m, 2H), 7.90 (m, 2H). M/Z for C₃₃H₄₈N₂O₆ [M+H]=569.

Example 2E90 Preparation of N-((1R,2R)-1-(4-(hexyloxy)phenyl)-1-hydroxy-3-((S)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 0.95 (t, 3H), 1.35 (m, 4H), 1.45 (m, 2H), 1.75 (m, 3H), 2.1 (m, 1H), 2.4 (m, 1H), 2.55 (t, 2H), 2.75 (m, 3H), 2.85 (m, 1H), 3.0 (m, 1H), 3.75 (s, 3H), 3.90 (t, 2H), 4.05 (m, 2H), 4.1 (m, 1H), 4.15 (m, 1H), 5.0 (br, 1H), 6.6 (br, 1H), 6.8 (m, 6H), 7.2 (m, 2H). M/Z for C₂₉H₄₂N₂O₆ [M+H]=515.

Example 2E91 Preparation of 2-(4′-chlorobiphenyl-4-yl)-N-((1R,2R)-3-((R)-3-fluoropyrrolidin-1-yl)-1-hydroxy-1-(4-isopropoxyphenyl)propan-2-yl)acetamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.15 (m, 6H), 2.10 (m, 2H), 2.4 (q, 1H), 2.5-2.75 (m, 4H), 2.95 (m, 2H), 3.55 (d, 2H), 4.15 (m, 1H), 4.45 (m, 1H), 4.85 (br, 1H), 5.10 (m, 1H), 5.9 (br, 1H), 6.75 (m, 2H), 7.05 (br, 2H), 7.20 (m, 2H), 7.4 (m, 2H), 7.5 (m, 4H). M/Z for C₃₀H₃₄ClFN₂O₃ [M+H]=528.

Example 2E92 Preparation of N-((1R,2R)-1-hydroxy-3-((S)-3-hydroxypyrrolidin-1-yl)-1-(4-isopropoxyphenyl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm): 1.35 (d, 6H), 1.7 (m, 1H), 2.1 (m, 1H), 2.45 (m, 1H), 2.55 (t, 2H), 2.7-2.9 (m, 4H), 3.0 (m, 1H), 3.8 (s, 3H), 4.05 (m, 1H), 4.15 (m, 1H), 4.20 (m, 1H), 4.35 (m, 1H), 4.5 (m, 1H), 4.95 (d, 1H), 6.55 (br, 1H), 6.75-6.85 (m, 6H), 7.2 (m, 2H). M/Z for C₂₆H₃₆N₂O₆ [M+H]=473.

Example 2E93 Preparation of N-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-5-(4-methoxyphenyl)-5-oxopentanamide

¹H NMR (400 MHz, CDCl₃) δ=1.7-2.2 (m, 12H), 2.4 (dd, 1H), 2.65-2.9 (m, 6H), 3.0 (dd, 1H), 3.90 (s, 3H), 3.91 (dd, 2H), 4.1-4.22 (m, 1H), 4.3-4.4 (m, 1H), 4.4 (dd, 1H), 4.6 (dd, 1H), 4.91 (d, 1H), 6.19 (d, 1H), 6.83 (d, 2H), 6.92 (d, 2H), 7.22 (d, 2H), 7.9 (d, 2H); MS for C₂₉H₃₉FN₂O₆ m/z 531 [M+H].

Example 2E94 Preparation of N-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-8-methoxyoctanamide

¹H NMR (400 MHz, CDCl₃) δ=1.2-1.34 (m, 6H), 1.45-1.6 (m, 4H), 1.7-1.8 (m, 1H), 1.86-1.95 (m, 4H), 2.0-2.2 (m, 4), 2.4-2.5 (m, 2H), 2.7-2.8 (m, 4H), 2.98 (dd, 1H), 3.3 (s, 3H), 3.53 (dd, 1H), 4.0 (dd, 2H), 4.1-4.2 (m, 1H), 4.3-4.4 (m, 1H), 4.5 (dd, 1H), 4.58 (dd, 1H), 4.9 (d, 1H), 5.9 (d, 1H), 6.85 (d, 2H), 7.22 (d, 2H); MS for C₂₆H₄₃FN₂O₅ m/z 483 [M+H]

Example 2E95 Preparation of N-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-4-(4-methoxyphenoxy)butanamide

¹H NMR (400 MHz, CDCl₃) δ=1.6-2.2 (m, 9H), 2.3-2.5 (m, 4H), 2.6-2.8 (m, 5), 2.9 (dd, 1H), 3.7 (s, 3H), 3.85 (dd, 2H), 3.95 (dd, 2H), 4.2-4.3 (m, 2H), 4.5 (dd, 1H), 4.6 (dd, 1H), 4.9 (d, 1H), 6.0 (d, 1H), 6.7-7 (m, 6H), 7.1-7.2 (d, 2H); MS for C₂₈H₃₉FN₂O₆ m/z 519 [M+H].

Example 2E96 Preparation of N-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (400 MHz, CDCl₃) δ=1.6-1.7 (m, 1H), 1.8-2 (m, 4H), 2.1-2.2 (m, 1), 2.4-2.5 (m, 1H), 2.6 (t, 2H), 2.7-2.85 (m, 4H), 3.0 (dd, 1H), 3.7 (s, 3H), 4.0 (t, 2H), 4.1-4.3 (m, 4H), 4.5 (dd, 1H), 4.6 (dd, 1H) 4.98 (d, 1H), 6.6 (d, 1H), 6.7-6.9 (m, 6H), 7.1-7.22 (d, 2H); MS for C₂₇H₃₇FN₂O₆ m/z 505[M+H].

Example 2E97 Preparation of N-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-7-(4-methoxyphenyl)-7-oxoheptanamide

¹H NMR (400 MHz, CDCl₃) δ=1.1-1.4 (m, 3H), 1.5-2.0 (m, 12H), 2.1-2.2 (dd, 4H), 2.4-2.90 (m, 10H), 3.0 (dd, 1H), 3.75 (s, 3H), 3.9 (dd, 2H), 4.1-4.2 (m, 1H), 4.3-4.4.5 (m, 2H), 4.57 (dd, 1H), 4.9 (d, 1H), 5.9 (d, 1H), 6.8 (d, 2H), 6.9 (d, 2H), 7.2 (d, 2H), 7.9 (d, 2H); MS for C₃₁H₄₃FN₂O₆ m/z 559[M+H].

Example 2E98 Preparation of N-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

¹H NMR (400 MHz, CD₃OD) δ=1.4-1.6 (m, 4H), 1.6-1.8 (m, 5H), 2.0-2.2 (m, 1H), 2.2-2.3 (m, 2H), 2.4-2.6 (m, 3H), 2.7-3.0 (m, 5H), 3.8 (s, 3H), 3.9 (dd, 1H), 4.1-4.25 (m, 1H), 4.3-4.38 (m, 1H), 4.4 (dd, 1H), 4.5 (dd, 1H), 6.8 (d, 2H), 7.1 (d, 2H), 7.2 (d, 2H), 8 (d, 2H); MS for C₃₀H₄₁FN₂O₆ m/z 545[M+H]

Example 2E99 Preparation of N-((1S,2R)-1-(5-chlorothiophen-2-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (400 MHz, CDCl₃) δ=1.7 (broad s, 4H), 2.5-2.7 (m, 7H), 2.8 (dd, 1H), 2.94 (dd, 1H), 3.77 (s, 3H) 4.1-4.2 (m, 2H), 4.3-4.35 (m, 1H), 5.18 (d, 1H), 6.55 (d, 1H), 6.66 (d, 1H), 6.67 (d, 1H), 6.7-6.9 (m, 4H); MS for C₂₁H₂₇ClN₂O₄S m/z 439[M+H].

Example 2E100 Preparation of N-((1S,2R)-1-hydroxy-1-(3-methylthiophen-2-yl)-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide 2,2,2-trifluoroacetate

¹H NMR (400 MHz, CD₃OD) δ=1.8-2.2 (m, 4H), 2.24 (s, 3H) 2.5-2.8 (m, 2H), 3.0-3.2 (m, 2H), 3.5 (dd, 2H), 3.7 (s, 3H), 3.6-3.8 (m, 2H), 4.0-4.2 (m, 2H), 4.5 (dd, 1H), 5.2 (s, 1H), 6.8 (d, 1H), 6.84 (broad s, 4H), 7.2 (d, 1H); MS for C₂₂H₃₀H₂O₄S m/z 419[M+H].

Example 2E101 Preparation of Compound 257: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-morpholinopropan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (400 MHz, CDCl₃) δ=2.4-2.6 (m, 7H), 2.7 (dd, 1H), 3.5-3.7 (m, 4H), 3.8 (s, 3H), 4-4.2 (m, 2H), 4.2 (s, 4H), 4.2-4.3 (m, 1H), 4.9 (d, 1H), 6.5 (d, 1H), 6.7-6.9 (m, 7H); MS for C₂₅H₃₂N₂O₇ m/z 473.1 [M+H].

Example 2E102 Preparation of Compound 261: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(piperidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

¹H NMR (400 MHz, CDCl₃) δ=1.4 (br, 2H), 1.6 (br, 4H), 2.2-2.8 (m, 6H), 3.8 (s, 3H), 4.0-42 (m, 2H), 4.2 (s, 4H), 4.2-4.3 (m, 1H), 4.9 (s, 1H), 6.4 (d, 1H), 6.7-6.9 (m, 7H); MS for C₂₅H₃₄N₂O₆ m/z 471.1 [M+H].

Example 2B1 Preparation of Compound 6: 1-benzyl-3-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.6 (m, 5H), 2.6-2.7 (dd, 1H), 4.0 (m, 1H), 4.2 (s, 4H), 4.3 (m, 2H), 4.8 (d, 1H), 4.86 (d, 1H), 5.0 (br, 1H), 6.6-6.9 (m, 3H), 7.2-7.4 (m, 5H); MS for C₂₃H₂₉N₃O₄ m/z 412.2 [M+H].

Example 2B2 Preparation of Compound 17: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-fluorobenzyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.4-2.6 (m, 6H), 3.9 (m, 1H), 4.0-4.1 (m, 2H), 4.13 (s, 4H), 4.7 (d, 1H), 5.4 (d, 1H), 6.6-7.1 (m, 7H); MS for C₂₃H₂₈FN₃O₄ m/z 430.2 [M+H].

Example 2B3 Preparation of Compound 40:1-(4-bromobenzyl)-3-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.8 (m, 6H), 4.0 (m, 1H), 4.1-4.2 (m, 2H) 4.2 (s, 4H), 4.8 (d, 1H), 5.3 (d, 1H), 5.6-5.8 (br, 1H), 6.8-7.0 (m, 3H), 7.0 (d, 2H), 7.4 (d, 2H); MS for C₂₃H₂₈BrN₃O₄ m/z 490 [M], 491 [M+H], 492 [M+2].

Example 2B4 Preparation of Compound 41: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxybenzyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.4-2.6 (m, 6H), 3.7 (s, 3H), 3.9 (m, 1H), 4.1 (d, 2H), 4.2 (s, 4H), 4.7 (d, 1H), 5.2 (d, 1H), 5.5-5.7 (br, 1H), 6.6-6.8 (m, 5H), 7.1 (d, 2H); MS for C₂₄H₃₁N₃O₅ m/z 442.2 [M+H].

Example 2B5 Preparation of Compound 80:1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(3-methoxybenzyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.6 (m, 6H), 3.8 (s, 3H), 4.0 (m, 1H), 4.1-4.2 (s, 6H), 4.8 (d, 1H), 5.1 (d, 1H), 5.2-5.4 (br, 1H), 6.6-6.8 (m, 6H), 7.2 (dd, 1H); MS for C₂₄H₃₁N₃O₅ m/z 442.2 [M+H].

Example 2B6 Preparation of Compound 42: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methylbenzyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.3 (s, 3H), 2.4-2.6 (m, 6H), 4.0 (m, 1H), 4.2 (d, 2H), 4.21 (s, 4H), 4.7 (d, 1H), 5.2 (d, 1H), 5.4-5.6 (br, 1H), 6.7-7.1 (m, 7H); MS (for C₂₄H₃₁N₃O₄ m/z 426.2 [M+H].

Example 2B7 Preparation of Compound 43: 1-(4-chlorobenzyl)-3-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.5-2.7 (m, 6H), 4.0 (m, 1H), 4.2 (s, 6H), 4.8 (d, 1H), 5.2 (d, 1H), 5.4-5.5 (br, 1H), 6.7-6.9 (m, 3H), 7.1 (d, 2H), 7.3 (d, 2H); MS for C₂₃H₂₈N₃ClO₄ m/z 446 [M+H], 447.5 [M+2].

Example 2B8 Preparation of Compound 10:1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(S)-1-phenylethyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.4 (d, 3H), 1.6 (s, 4H), 2.2-2.5 (m, 4H), 2.5 (dd, 1H), 2.6 (dd, 1H), 3.9 (m, 1H), 4.2 (s, 4H), 4.5 (m, 1H), 4.8 (d, 1H), 5.0 (d, 1H), 5.1-5.3 (br, 1H), 6.6-6.9 (m, 3H), 7.2-7.4 (m, 5H); MS for C₂₄H₃₁N₃O₄ m/z 426.2 [M+H].

Example 2B9 Preparation of Compound 286: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(®-1-phenylethyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.3 (d, 3H), 1.7 (s, 4H), 2.2-2.6 (m, 6H), 3.9 (m, 1H), 4.2 (s, 4H), 4.6-4.7 (m, 2H), 5.3 (d, 1H), 5.6-5.7 (br, 1H), 6.6 (d, 1H), 6.7 (d, 1H), 6.8 (s, 1H), 7.2-7.4 (m, 5H); MS for C₂₄H₃₁N₃O₄ m/z 426.0 [M+H].

Example 2B10 Preparation of Compound 69: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(naphthalen-2-yl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.4-2.8 (m, 6H), 4.1 (s, 5H), 4.8 (s, 1H), 6.0 (d, 1H), 6.7 (s, 2H), 6.9 (s, 1H), 7.1-7.8 (m, 7H); MS for C₂₆H₂₉N₃O₄ m/z 448.1 [M+H].

Example 2B11 Preparation of Compound 288: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(naphthalen-1-yl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.4 (s, 4H), 2.6 (d, 2H), 4.1 (m, 1H), 4.2 (s, 4H), 4.8 (d, 1H), 5.4 (d, 1H), 6.5 (d, 1H), 6.6 (d, 1H), 6.7 (s, 1H), 7.2-7.6 (m, 3H), 7.7 (d, 1H), 7.8 (d, 1H), 8.0 (d, 1H); MS for C₂₆H₂₉N₃O₄ m/z 448.1 [M+H].

Example 2B12 Preparation of Compound 71: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-((S)-1-(naphthalen-1-yl)ethyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.4 (s, 4H), 1.5 (d, 3H), 2.3 (s, 4H), 2.4 (dd, 1H), 2.6 (dd, 1H), 3.9 (br, 1H), 4.2 (s, 4H), 4.7 (s, 1H), 5.0 (d, 1H), 5.3 (br, 1H), 5.5 (br, 1H), 6.6 (m, 3H), 7.4-7.6 (m, 4H), 7.7 (d, 1H), 7.8 (d, 1H), 8.1 (d, 1H); MS for C₂₈H₃₃N₃O₄ m/z 476.2 [M+H].

Example 2B13 Preparation of Compound 70: 1-(biphenyl-4-yl)-3-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.6-2.8 (m, 6H), 4.1 (br, 1H), 4.2 (s, 4H), 4.9 (br, 1H), 5.9 (d, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2-7.6 (m, 9H); for C₂₈H₃₁N₃O₄ m/z 474.1 [M+H].

Example 2B14 Preparation of Compound 81: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(trifluoromethyl)phenyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.7 (m, 6H), 4.0 (br, 1H), 4.2 (s, 4H), 4.8 (br, 1H), 5.9 (br, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.3 (d, 2H), 7.5 (d, 2H); MS for C₂₃H₂₆F₃N₃O₄ m/z 465.97 [M+H].

Example 2B15 Preparation of Compound 68: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(3-(trifluoromethyl)phenyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.5-2.9 (m, 6H), 4.0 (br, 1H), 4.2 (s, 4H), 4.8 (br, 1H), 5.9 (br, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2-7.6 (m, 4H); MS for C₂₃H₂₆F₃N₃O₄ m/z 466.0 [M+H].

Example 2B16 Preparation of Compound 82: 1-1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.7 (m, 6H), 4.0 (br, 1H), 4.2 (s, 4H), 4.8 (br, 1H), 5.9 (br, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.0 (d, 2H), 7.2 (d, 2H); MS for C₂₃H₂₆F₃N₃O₅ m/z 481.5 [M], 482.5 [M+H].

Example 2B17 Preparation of Compound 133: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(2-methylthiazol-4-yl)phenyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.7 (m, 6H), 2.7 (s, 3H), 4.1 (br, 1H), 4.2 (s, 4H), 4.8 (br, 1H), 5.9 (d, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2 (s, 1H), 7.3 (d, 2H), 7.7 (d, 2H); MS for C₂₆H₃₀N₄O₄S m/z 494.9 [M+H].

Example 2B18 Preparation of Compound 7: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-dodecylurea

¹H NMR (400 MHz, CDCl₃) δ=0.9 (t, 3H), 1.3 (br, 18H), 1.4 (m, 2H), 1.8 (s, 4H), 2.5-2.7 (m, 6H), 3.1 (q, 2H), 4.0 (m, 1H), 4.3 (s, 4H), 4.4 (br, 1H), 4.76 (d, 4.8 (d, 1H), 6.7-6.8 (dd, 2H), 6.9 (s, 1H); MS for C₂₈H₄₇N₃O₄ m/z 489.7 [M+H], 490.9 [M+2].

Example 2B19 Preparation of Compound 287: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(2-(thiophen-2-yl)ethyl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.5-2.7 (m, 6H), 3.0 (t, 2H), 3.8 (q, 2H), 4.0 (m, 1H), 4.2 (s, 4H), 4.8 (d, 2H), 4.9 (d, 1H), 6.7-6.8 (m, 3H), 6.9 (d, 1H), 6.9 (dd-1H), 7.1 (d, 1H); MS for C₂₂H₂₉N₃O4S m/z 432.1 [M+H].

Example 2B20 Preparation of 1-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-3-(4-methoxybenzyl)urea 2,2,2-trifluoroacetate

¹H NMR (400 MHz, CD₃OD) δ=1.8-2.2 (m, 6H), 3.2-3.3 (dd, 2H), 3.4-3.7 (m, 3H), 3.8 (s, 3H), 3.82-4.1 (m, 4H), 4.3 (dd, 2H), 4.4 (dd, 1H), 4.5 (dd, 2H), 4.8 (dd, 1H), 6.8 (d, 2H), 6.9 (d, 2H), 7 (m, 2H), 7.3 (d, 2H); MS for C₂₆H₃₆FN₃O₅ m/z 491[M+H].

Example 2B21. Preparation of 1-(4-chlorobenzyl)-3-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)urea

¹H NMR (400 MHz, CDCl₃) δ=1.6-1.8 (m, 3H), 1.8-2 (m, 5H), 2-2.2 (m, 2H), 2.2-2.3 (m, 2H), 2.8-2.4 (m, 5H), 2.9 (m, 1H), 3.9-4.0 (m, 3), 4.1-4.4 (m, 3H), 4.5 (t, 1H), 4.6-4.7 (m, 1H), 4.75 (d, 1H), 6.8 (d, 2H), 7.1 (d, 2H), 7.15-7.3 (m, 4H); MS for C₂₅H₃₃ClFN₃O₄ m/z 494[M+H].

Example 3 GM3 Elisa Assay

B16-FO cells from ATCC (American Tissue Culture Collection) were grown in DMEM media (ATCC) with 10% Fetal Bovine Serum (Hyclone) and Pen/Step/Glutamine (Biowhittaker). 4000 cells per well were plated on collagen coated plates (BD) and allowed to attach for 6 hours in an incubator (37 degrees, 5% CO2). After 6 hours the compounds and controls were added to the wells, the plates mixed and returned to the incubator for 2 days. Day of assay the cells were fixed for 20 minutes with 1% formaldehyde and then washed with Tris Buffered Saline (TBS) 3 times, 150 μl of TBS was left in the wells and 50 μl of goat serum (Invitrogen) was added, the plates mixed and incubated for 1 hour at room temperature. The plates were flicked and the cells incubated with the monoclonal Antibody to GM3 (NeuAc) (Cosmo) for 45 minutes as room temperature. The plates were then washed 3 times with TBS, leaving 150 μl of TBS in the wells and Peroxidase AffinPure F (ab′) 2 frag Gt Anti-mouse IgM, μ Chain Specific (Jackson Immno Research) was added in 50 μl, the plates mixed and incubated for 45 minutes at room temperature. The plates were washed 3 times with TBS, flicked and blotted and 100 μl of Quantablu (Pierce) was added to the wells and incubated for 1 hour then read on a Fluorometer at Ex 325 and Em 420. The data was then analyzed using standard programs.

The results of the GM3 Elisa assay are summarized in Tables 1-3. In Tables 1-3, IC50 values are indicated as “A,” “B,” C,” “D,” and “E” for those of less than or equal to 0.1 μm; those of greater than 0.1 μm, and less than or equal to 1 μm; those of greater than 1 μm, and less than or equal to 3 μm; those of greater than 3 μm, and less than or equal to 10 μm; those of greater than 10 μm, respectively. As shown in Tables 1-3, numerous compounds of the invention were shown to be inhibitors of GM3.

TABLE 1 IC 50 Values from GM3 Elisa Assay

Z—R* Compound IC50_uM_Mean

1 B

2 C

3 C

4 B

5 B

6 B

7 A

8 B

9 B

10 B

11 A

12 B

13 B

14 B

15 B

16 D

17 A

18 B

19 B

20 B

21 A

22 C

23 A

24 B

25 B

26 B

27 A

28 A

29 A

30 B

31 B

32 A

33 A

34 C

35 C

36 B

37 B

38 B

39 A

40 A

41 A

42 A

43 A

44 B

45 B

46 B

47 B

48 A

49 A

50 B

51 B

52 B

53 C

54 A

55 A

56 A

57 A

58 B

59 A

60 A

61 A

62 B

63 A

64 A

65 A

66 A

67 A

68 B

69 B

70 A

71 B

72 B

73 A

74 B

75 B

76 B

77 A

78 B

79 A

80 B

81 B

82 A

83 A

84 C

85 A

86 A

87 A

88 B

89 B

90 B

91 B

92 A

93 A

94 C

95 A

96 A

97 B

98 D

99 B

100 A

101 A

102 C

103 A

104 B

105 B

106 B

107 D

108 B

109 A

110 A

111 B

112 B

113 B

114 B

115 A

116 B

117 B

118 B

119 A

120 B

121 D

122 D

123 C

124 C

125 B

126 D

127 B

128 C

129 B

130 C

131 A

132 D

133 D

134 C

135 C

136 A

137 A

138 A

139 A

140 A

141 A

142 A

143 A

144 A

145 B

146 B

147 B

148 A

149 B

150 C

151 B

152 A

153 B

154 B

155 B

156 A

157 A

158 A

159 A

160 B

161 B

162 A

163 A

164 A

165 A

166 A

167 A

168 A

169 A

170 B

171 C

172 B

173 A

174 A

175 A

176 A

177 B

178 A

179 A

180 B

181 A

182 B

183 A

184 B

185 B

186 A

187 B

188 B

189 B

190 A

191 A

192 B

193 B

194 B

195 B

196 C

197 A

198 B

199 A

200 B

201 C

202 B

203 A

204 B

205 A

206 B

207 A

208 B

209 A

210 B

211 B

212 D

213 B

214 D

215 B

216 A

217 A

218 D

219 D

220 B

221 A

222 A

223 A

224 B

225 A

226 D

227 C

228 B

229 E

230 B

231 A

232 C

233 C

234 B

235 B

236 A

237 A

238 A

239 D

240 C

241 A

291 C

292 C

293 B

294 B

295 A

296 B

297 C

298 B

299 A

300 A

301 A

302 A

303 A

304 A

305 A

306 B

307 A

308 A

TABLE 2 IC 50 Values from GM3 Elisa Assay Structure Compound IC50_uM_Mean

242 D

243 A

244 A

245 D

246 C

247 A

248 B

249 C

250 B

251 B

252 B

253 B

254 B

255 C

256 B

257 D

258 D

259 A

260 A

261 B

262 A

263 B

264 A

265 A

266 A

267 A

268 A

269 A

270 A

271 A

272 A

273 B

274 C

275 A

276 B

277 D

278 E

279 C

282 C

283 A

284 A

285 A

286 D

287 C

289 B

309 A

310 C

311 C

312 B

313 A

314 C

315 B

316 D

317 B

318 B

319 B

320 A

321 C

322 B

TABLE 3 IC 50 Values Com- Structure IC50_uM_Mean pound

B 340

A 341

B 342

B 343

A 344

A 345

B 346

B 347

B 348

B 349

A 350

B 351

D 352

B 353

B 354

C 355

C 356

B 357

A 358

B 359

B 360

D 361

D 362

B 363

A 364

A 365

A 366

A 367

A 368

A 369

A 370

A 371

A 372

A 373

A 374

B 375

A 376

A 377

A 378

B 379

A 380

C 381

B 382

B 383

B 384

C 385

B 386

B 387

A 388

A 389

A 390

B 391

D 392

D 393

C 394

D 395

D 396

D 397

D 398

C 399

D 400

B 401

D 402

C 403

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D 406

C 407

C 408

B 409

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A 412

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B 414

B 415

A 416

A 417

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A 420

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D 422

C 423

D 424

D 425

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D 427

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A 430

A 431

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A 436

A 437

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B 439

A 440

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B 444

B 445

A 446

A 447

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A 449

A 450

B 451

B 452

A 453

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A 455

A 456

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D 458

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C 460

B 461

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B 463

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D 466

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A 468

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B 470

C 471

B 472

A 473

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A 479

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B 494

A 495

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D 554

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C 558

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A 565

A 566

B 567

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D 569

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B 573

B 574

B 575

B 576

B 577

A 578

D 579

D 580

B 581

D 582

D 583

B 584

B 585

A 586

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D 591

A 592

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D 613

D 614

B 615

D 616

C 617

D 618

C 619

B 620

C 621

D 622

D 623

D 624

D 625

B 626

D 627

A 628

B 629

B 630

D 631

D 632

B 633

B 634

D 635

D 636

B 637

D 638

B 639

B 640

A 641

B 642

C 643

C 644

D 645

D 646

B 647

648

649

B 650

C 651

D 652

A 653

C 654

B 655

A 656

B 657

B 658

B 659

B 660

C 661

B 662

B 663

C 664

D 665

B 666

B 667

C 668

D 669

D 670

D 671

D 672

D 673

D 674

D 675

D 676

D 677

D 678

D 679

A 680

C 681

D 682

D 683

B 684

D 685

D 686

D 687

D 688

D 689

A 690

D 691

B 692

A 693

B 694

B 695

C 696

B 697

B 698

A 699

B 700

C 701

A 702

A 703

A 704

A 705

A 706

A 707

A 708

A 709

A 710

A 711

B 712

B 713

D 714

D 715

D 716

D 717

D 718

D 719

D 720

D 721

A 722

A 723

B 724

B 725

B 726

A 727

A 728

A 729

A 730

A 731

B 732

A 733

A 734

A 735

A 736

B 737

A 738

A 739

A 740

A 741

Example 4 Glucosylceramide Levels in Kidneys of Mouse Model of Collapsing Glomerulopathy

A transgenic mouse model Tg26 of collapsing glomerulopathy (CG) was assessed for changes in kidney and serum glucosylceramide levels. Production of the transgenic mice is described in Dickie et al., “HIV-Associated Nephropathy in Transgenic Mice Expressing HIV-1 Genes,” Virology, 185:109-119, 1991, the entire teachings of which are incorporated herein by reference. Tg26 mice progressively develop CG due to expression of HIV proteins present in the transgene, which results in progressively increasing proteinuria. Kidneys from these animals were collected. Animals were selected based on the level of proteinuria. Mice showing low but measurable urinary proteins (+reading) were designated early disease, while animals showing high levels of urinary protein (+++reading) were designated late disease. Non-transgenic littermates, used as controls, demonstrated no proteinuria (non/trace readings).

Hematoxylin and eosin stained kidney sections from early disease animals demonstrate many normal glomeruli (arrow in FIG. 1A) in addition to injured glomeruli (arrowhead in FIG. 1A). However, no microcyst formation was evident at this stage of disease. At late stages of disease, injured glomeruli predominate and microcysts are obvious (* in FIG. 1A).

Kidney and serum glucosylceramide (GlcCer) levels were measured from control, early, and late stage disease samples. Kidneys were homogenized in distilled water prior to glycosphingolipid extraction. Briefly, tissues were homogenized in water using a Mini Beadbeater (Biospec Products, Bartlesville, Okla.) following vendor's protocol. The tissue density was adjusted to 100 mg/mL prior to homogenization. The homogenate was immediately stored at −80° C. until ready for analysis.

Glycosphingolipids were extracted from kidney homogenates or serum samples with methanol/acetone and analyzed by reverse-phase HPLC/mass spectroscopy to determine relative GlcCer levels. First, sphingolipids were extracted with a modified Folch method (Folch, Lees and Stanley, J. Biol. Chem., 226:497-509, 1957, the entire teachings of which are incorporated herein by reference). Briefly, an aliquot of 140 μL tissue homogenate was mixed with 0.33 mL of deionized water, 1.7 mL methanol and 1.7 mL chloroform in a glass tube. The mixture was shaken overnight at room temperature. The supernatant was dried under a stream of nitrogen.

The dried sphingolipid extract was reconstituted in methanol/chloroform/water mixture. The solution was then diluted 5-fold in volume in the vial by a solution consisting of 3:1 methanol/chloroform, 0.2% (vol/vol) formic acid (FA) and 5 mM of ammonium formate (AmF). Separation of the sphingolipids was achieved with an Agilent 1100 HPLC system (Agilent, Palo Alto, Calif.) equipped with a Waters Xbridge Phenyl 3.0×100 mm 3.5 um column. The mobile phases were composed of 0.2% (v/v) FA and 5 mM AmF in water (A) and 0.2% FA (v/v) and 5 mM AmF in 1:1 methanol/acetonitrile (B). The flow rate was 0.6 mL/min. The gradient was as follows: 70% B to 100% B in 5 min, hold at 100% B for 3 min, reset. The column was heated to 60° C. The volume of injection was 5 μL. All solvents were purchased from Sigma and were analytical grade. Sphingolipid standards were purchased from Matreya (Pleasant Gap, Pa.).

The eluent from the HPLC was analyzed by electrospray ionization (ESI) mass spectrometry using an API-4000 mass spectrometer (Applied Biosystems, Forster City, Calif.). Measurements took place in positive ion mode. Typical ESI-MS conditions were: needle voltage, 3.5 kV; curtain gas, 20; GS1, 35; GS2, 35; drying gas temperature, 400° C., collision gas density (CAD), 7. DP and CE were optimized for individual multiple-reaction-monitoring (MRM) transitions for various glucosylceramide (GL1) isoforms as follows: C16:0, 700.6/264.2, DP=71, CE=47; C18:0, 728.7/264.2, DP=81, CE=51, C22:0, 784.7/264.2, DP=66, CE=50; C23:0, 798.7/264.2; DP=66, CE=50; C24:1, 810.7/264.2, DP=76, CE=57; C24:0, 812.7/264.2, DP=76, CE=57. The dwell time for all transition's was set to 75 ms. All MRM transitions included m/z 264.2 as the product ions. The data was processed with Analyst 1.4.2.

Total phosphate in the kidney extracts was measured by Inductively Coupled Plasma-Optical Emission Spectroscopy (ICP-OES) for normalization. Total phosphate analysis was based on the method developed by Jankowski (Jankowski, Microchem. J., 70:41-49, 2001, the entire teachings of which are incorporated herein by reference). The sphingolipid extract was subject to digestion in 15% nitric acid in a microwave oven (CEM Corp., MARS-5, Mathews, N.C.) using Food 1 program. The digest was then analyzed using ICP-OES (Varian Instruments, Walnut Creek, Calif.). The readout wavelength was selected at 213.618 nm.

Total phosphotidylcholine analysis was performed as follows. Briefly, reconstituted sphingolipid extract was diluted by 100-fold with mobile phase A (see below). Separation of the various isoforms of phosphatidylcholine (PC) was achieved with an Agilent 1100 HPLC system (Agilent, Palo Alto, Calif.) equipped with a Phenomenex Luna 3 um HILIC 100×2.0 mm 3 um column (Phenomenex, Torrance, Calif.). The mobile phases were composed of 1% (v/v) AA and 5 mM AmA in a mixture of methanol/acetonitrile/water in a volume ratio of 2:97:1 (A), and in methanol containing 1% AA, 5 mM AmA and 1% water (B). The flow rate was 0.25 mL/min The gradient was as follows: 0% B from 0 to 0.5 min., 0% B to 50% B from 0.5 min to 3 min, 100 B % at 3.01 min, hold at 100% B for 1 min., reset. The column was heated to 45° C. The volume of injection was 3 μL. All solvents were purchased from Sigma and were analytical grade. Sphingolipid standards were purchased from Matreya (Pleasant Gap, Pa.). The eluent from the HPLC was analyzed by ESI-MS using an API3000 mass spectrometer (Applied Biosystems, Forster City, Calif.). Measurements took place in positive ion mode. Precursor ion scan (PIS) was used in order to capture all isoforms, with the product ion m/z set to 184.2. Typical ESI-MS conditions were: needle voltage, 4.0 kV; curtain gas, 8; Neb, 12; GS1, 35; GS2, 35; drying gas temperature, 400° C., collision gas density (CAD), 7; DP, 40; and CE at 55. The data was processed with Analyst 1.4.2.

It was found that serum levels were similar in control, early-state and late state disease animals. Kidney GlcCer is elevated even at early stages of disease, only slightly increasing later in the disease process. This increase precedes extreme proteinuria and microcyst formation. 

What is claimed is:
 1. A method of treating a glomerular disease selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis and membranous nephropathy in a subject, comprising administering to the subject an effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_(o)—OR³⁰, —V_(o)—N(R³¹)₂, —V_(o)—Ar¹, —O—V_(o)—Ar¹, —O—V₁—N(R³¹)₂, —S—V_(o)—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_(o)—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_(p)—O—, —S—[CH₂]_(p)—S—, and —[CH₂]_(q)—; Ar¹ is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and each R³⁰ is independently i) hydrogen; ii) a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or iii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and each R³¹ is independently R³⁰, or —N(R³¹)₂ is an optionally substituted non-aromatic heterocyclic group; R² and R³ taken together with the nitrogen atom of N(R²R³) form a pyrrolidinyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; R⁴ is an aliphatic or aryl group, each optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar³, Ar³—Ar³, —OR⁵⁰, —O(haloalkyl), —SR⁵⁰, —NO₂, —CN, —NCS, —N(R⁵¹)₂, —NR⁵¹C(O)R⁵⁰, —NR⁵¹C(O)OR⁵², —N(R⁵¹)C(O)N(R⁵¹)₂, —C(O)R⁵⁰, —C(S)R⁵⁰, —C(O)OR⁵⁰, —OC(O)R⁵⁰, —C(O)N(R⁵¹)₂, —S(O)₂R⁵⁰, —SO₂N(R⁵¹)₂, —S(O)R⁵², —SO₃R⁵⁰, —NR⁵¹SO₂N(R⁵¹)₂, —NR⁵¹SO₂R⁵², —V₄—Ar³, —V—OR⁵⁰, —V₄—O(haloalkyl), —V₄—SR⁵⁰, —V₄—NO₂, —V₄—CN, —V₄—N(R⁵¹)₂, —V₄—NR⁵¹C(O)R⁵⁰, —V₄—NR⁵¹CO₂R⁵², —V₄—N(R⁵¹)C(O)N(R⁵¹)₂, —V₄—C(O)R⁵⁰, —V₄—C(S)R⁵⁰, —V₄—CO₂R⁵⁰, —V₄—OC(O)R⁵⁰, —V₄—C(O)N(R⁵¹)₂—, —V₄—S(O)₂R⁵⁰, —V₄—SO₂N(R⁵¹)₂, —V₄—S(O)R⁵², —V₄—SO₃R⁵⁰, —V₄—NR⁵¹SO₂N(R⁵¹)₂, —V₄—NR⁵¹SO₂R⁵², —O—V₄—Ar³, —O—V₅—N(R⁵¹)₂, —S—V₄—Ar³, —S—V₅—N(R⁵¹)₂, —N(R⁵¹)—V₄—Ar³, —N(R⁵¹)—V₅—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—Ar³, —C(O)—V₄—N(R⁵¹)₂, —C(O)—V₄—Ar³, —C(S)—V₄—N(R⁵¹)₂, —C(S)—V₄—Ar³, —C(O)O—V₅—N(R⁵¹)₂, —C(O)O—V₄—Ar³, —O—C(O)—V₅—N(R⁵¹)₂, —O—C(O)—V₄—Ar³, —C(O)N(R⁵¹)—V₅—N(R⁵¹)₂, —C(O)N(R⁵¹)—V₄—Ar³, —S(O)₂—V₄—N(R⁵¹)₂, —S(O)₂—V₄—Ar³, —SO₂N(R⁵¹)—V₅—N(R⁵¹)₂, —SO₂N(R⁵¹)—V₄—Ar³, —S(O)—V₄—N(R⁵¹)₂, —S(O)—V₄—Ar³, —S(O)₂—O—V₅—N(R⁵¹)₂, —S(O)₂—O—V₄—Ar³, —NR⁵¹SO₂—V₄—N(R⁵¹)₂, —NR⁵¹SO₂—V₄—Ar³, —O—[CH₂]_(p′)—O—, —S—[CH₂]_(p′)—S—, and —[CH₂]_(q′)—; each V_(o) is independently a C1-C10 alkylene group; each V₁ is independently a C2-C10 alkylene group; each V₄ is independently a C1-C10 alkylene group; each V₅ is independently a C2-C10 alkylene group; R⁵ and R⁶ are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group; each R⁵⁰ is independently (i) hydrogen; (ii) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or (iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; each R⁵¹ is independently R⁵⁰, —CO₂R⁵⁰, —SO₂R⁵⁰ or —C(O)R⁵⁰, or —N(R⁵¹)₂ taken together is an optionally substituted non-aromatic heterocyclic group; each R⁵² is independently (i) an aryl group optionally substituted with one or two substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or (ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; Q is —O—, —S—, —C(O)—, —C(S)—, —NR⁷(CO)— or —C(O)NR⁷—; Ar¹ is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; each Ar³ is independently an aryl group, each optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl; n is 1, 2, 3, 4, 5 or 6; each p is independently 1, 2, 3 or 4; each p′ is independently 1, 2, 3 or 4; each q is independently 3, 4, 5 or 6; and each q′ is independently 3, 4, 5 or
 6. 2. The method of claim 1, wherein the glomerular disease is mesangial proliferative glomerulonephritis.
 3. The method of claim 1, wherein the glomerular disease is collapsing glomerulopathy.
 4. The method of claim 1, wherein the glomerular disease is proliferative lupus nephritis.
 5. The method of claim 1, wherein the glomerular disease is crescentic glomerulonephritis.
 6. The method of claim 1, wherein the glomerular disease is membranous nephropathy.
 7. The method of claim 1, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: Q is —O—, —C(O)— or —NH; n is 1, 2, 3, 4, 5 or 6; r is 1, 2, 3 or 4; and s is
 1. 8. The method of claim 1, wherein Q is —O— or —C(O)—.
 9. The method of claim 8, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 10. The method of claim 8, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 11. The method of claim 1, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: R⁴ is an optionally substituted lower alkyl group or an optionally substituted aryl group; B is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; Q is —O—, —C(O)— or —NH; n is 1, 2, 3, 4, 5, or 6; r is 1, 2, 3 or 4; s is 1; and k″ is 0 or
 1. 12. The method of claim 11, wherein Q is —O— or —C(O)—.
 13. The method of claim 12, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 14. The method of claim 1, wherein R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_(p)—O— and —[CH₂]_(q)—.
 15. The method of claim 14, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 16. The method of claim 14, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 17. The method of claim 14, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 18. The method of claim 14, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 19. The method of claim 14, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 20. The method of claim 14, wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 21. The method of claim 1, wherein the compound is a (1R,2R) stereoisomer, or a pharmaceutically acceptable salt thereof.
 22. A method of treating a glomerular disease selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis and membranous nephropathy in a subject, comprising administering to the subject an effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 23. A method of treating a glomerular disease selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis and membranous nephropathy in a subject, comprising administering to the subject an effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: —(CH₂)_(n)—R⁴ is a C6-C8 straight chained alkyl group optionally substituted with hydroxy; B is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; r and s are each independently 1, 2, 3 or 4; and k″ is 0 or
 1. 24. The method of claim 23, wherein the compound is a (1R,2R) stereoisomer, or a pharmaceutically acceptable salt thereof. 